Journal of Immunology Research

Journal of Immunology Research / 2017 / Article

Review Article | Open Access

Volume 2017 |Article ID 2528957 |

Minwen Xu, Xiaoli Zhang, Ruiyun Hong, Dong-Ming Su, Liefeng Wang, "MicroRNAs Regulate Thymic Epithelium in Age-Related Thymic Involution via Down- or Upregulation of Transcription Factors", Journal of Immunology Research, vol. 2017, Article ID 2528957, 9 pages, 2017.

MicroRNAs Regulate Thymic Epithelium in Age-Related Thymic Involution via Down- or Upregulation of Transcription Factors

Academic Editor: Luca Gattinoni
Received19 Apr 2017
Revised09 Aug 2017
Accepted20 Aug 2017
Published10 Sep 2017


Age-related thymic involution is primarily induced by defects in nonhematopoietic thymic epithelial cells (TECs). It is characterized by dysfunction of multiple transcription factors (TFs), such as p63 and FoxN1, and also involves other TEC-associated regulators, such as Aire. These TFs and regulators are controlled by complicated regulatory networks, in which microRNAs (miRNAs) act as a key player. miRNAs can either directly target the 3-UTRs (untranslated regions) of the TFs to suppress TF expression or target TF inhibitors to reduce or increase TF inhibitor expression and thereby indirectly enhance or inhibit TF expression. Here, we review the current understanding and recent studies about how miRNAs are involved in age-related thymic involution via regulation of TEC-autonomous TFs. We also discuss potential strategies for targeting miRNAs to rejuvenate age-related declined thymic function.

1. Introduction

The ubiquitous and abundant existence of small noncoding microRNAs (miRNAs) in worms, plants, and animals play an important role in the regulation of gene expression, which primarily occurs at posttranscriptional levels via cleavage and/or translational repression of messenger RNAs (mRNAs) [1]. Ample evidence shows that miRNAs control a wide range of developmental and physiological pathways, including cell proliferation [2], differentiation [3], and apoptosis [4]. Thus, deregulation of miRNAs will cause certain developmental obstructions, deficiencies, and even the onset of diseases [5]. The miRNA regulation is also engaged in several aspects of thymic biology [6], which are critical for T lymphopoiesis. The entire process of thymus organogenesis, maturation, and age-related involution is tightly regulated by transcription factors (TFs) [7], which, in turn, could be regulated at posttranscriptional level by miRNA genes [8, 9]. The thymus is composed of mainly hematopoietic thymocytes and nonhematopoietic thymic epithelial cells (TECs). TECs play a key role in supporting thymocyte development and controlling thymic aging. Although thymocytes possess their own transcription factors (TFs) to control their autonomous activities, many thymic activities during thymic development and aging can be regulated by known TFs in TECs, such as the p63 and FoxN1 [1013]. However, regulation of these TFs remains mysterious and there is limited evidence as to the mechanisms involved. Given that many miRNAs are expressed in the thymus with different expression profiles at different developmental stages, we have adequate reasons to infer that miRNAs can be responsible for the regulation of TFs which are involved in maintaining normal thymic microenvironment that supports T lymphocyte development and controls age-related thymic involution. In this review, we focus on recent research progress which helps to elucidate how miRNA genes regulate TEC homeostasis and aging by affecting TEC-specific TFs. This summary about miRNA-mediated regulation will provide us some new insights into the regulatory networks underlying the construction and maintenance of the thymic microenvironment during thymic aging and even provide potential strategies for rejuvenating the function of the aged thymus.

2. Thymic Stromal Cell Homeostasis, Thymic Aging, and Transcriptional Regulation

The thymus is one of the most important organs in animal life. It generates T lymphocytes and supports the cellular immune system involved in the activities of antitumor, antivirus, and anti-intracellular infection, as well as in the establishment of self-tolerance to prevent autoimmune diseases. The thymus is also one of the most active organs, as it undergoes organogenesis (cell migration, proliferation, and differentiation), development (proliferation, differentiation, and cell apoptosis), and age-related involution (cell senescence and apoptosis) [14]. The aging process in the thymus starts in early adolescent years, and the typical thymic aging phenotype is thymic involution [15, 16].

There are two progenitor cell types in the thymus, hematopoietic thymocytes and nonhematopoietic TECs [17]. They interact and regulate each other in thymic development, homeostasis, and aging. Both cell types undergo a stepwise or sequential developmental process [18, 19]. In principle, TECs play a primary role in constructing the three-dimensional thymic meshwork and maintain the thymic microenvironment to support T cell development. TEC development and homeostasis are critical for determining thymic organogenesis prenatally and also regulate thymic involution during aging [20, 21].

Age-related thymic involution does not only reduce the output of naïve T cells but also increase the release of self-reactive T cells from the thymus [22]. These age-related changes create the basis for many age-related diseases, such as immunosenescence, chronic inflammatory diseases, including cardiovascular and neurodegenerative diseases, autoimmunity, and cancer. Age-related thymic involution appears to be a defect primarily associated with TECs [23]. TEC development and homeostasis are very meticulous processes controlled by complex regulatory networks during thymus organogenesis, homeostasis, and aging [24], which involved multiple signaling pathways and cellular interactions. Transcription factors FoxN1 and p63 are crucial for TEC development. In the thymus, FoxN1, which plays an important role in TEC survival and differentiation [25, 26], promotes differentiation of thymic epithelial progenitor cells into functional medullary thymic epithelial cells (mTECs) and cortical thymic epithelial cells (cTECs) during organogenesis [27, 28] and maintains postnatal TEC homeostasis [29, 30]. The transcription factor p63 plays a crucial role for the epithelial development in several tissues, such as thymus and epidermis [31], and is essential for the proliferative potential of thymic epithelial progenitor cells [31, 32]. There are two p63 isoforms: one containing an N-terminal transactivation domain, named TAp63, while the other lacking this domain is named ΔNp63. ΔNp63 and FoxN1 are both highly expressed in the fetal thymus [11, 33], but, in the adult thymus, both FoxN1+ and ΔNp63+ TECs are decreased with age [10, 34, 35]. So far, the mechanism underlying this decline is largely unknown.

Another very important transcription factor expressed in mTECs is the autoimmune regulator (Aire) gene; the expression of which is also declined with age [36, 37]. Although it is uncertain whether Aire functions to regulate the differentiation of immature TECs [38], its role in regulating clonal deletion of self-reactive T cells is definite [39, 40]. Although thousands of target genes induced by Aire have already been identified and well characterized, the regulation of Aire gene itself remains elusive. Recently, many regulators which might act upstream of Aire have been identified [41]. For example, a FoxN1-Cre-induced ablation of DGCR8, a component of the miRNA-specific microprocessor complex, eliminated Aire expression in TECs, implying a potential role of miRNA in the regulation of Aire gene, since DGCR8 participates in the pri-miRNA to pre-miRNA processing [42, 43]. However, the specific miRNAs involved in Aire regulation and the mechanisms by which they modulate Aire expression need further investigation.

3. A Fine-Tuning Role of miRNAs in Thymic Epithelial Cell Homeostasis

The miRNAs are posttranscriptional regulators involved in transcriptional repression or enhancement. Notably, a single miRNA can regulate multiple genes and a single gene can be regulated by multiple miRNAs [44]. Gene expression can be turned on either by TFs or indirectly by downregulation of other suppressive genes [45]. Expression of TFs can be suppressed either by miRNAs at their 3-UTRs or by other suppressive genes. The suppressive genes can also be regulated by miRNAs [46]. A diagram of this regulatory network is schematically shown in Figure 1. Therefore, miRNAs play a fine-tuning role by targeting mRNAs of both TFs (direct suppression) and TF suppressors (indirect enhancement) for cleavage, translational repression, or chromatin modification [4749]. miRNAs function in a wide range of biological process including developmental regulation [5052], hematopoietic cell lineage determination [5355], cellular proliferation and death/apoptosis [5661], fat metabolism [62, 63], neuronal patterning in nematodes [64, 65], chemosensory neurons asymmetric expression [64, 66], and oncogenesis [6770].

Since expression of miRNAs is tightly related to tissue differentiation stages [71] and miRNAs can function to prevent cell division and drive terminal differentiation [72], miRNAs are very likely to be involved in TEC differentiation-driven thymic development and thymic involution [73]. For a given gene, its expression could be directly suppressed by some miRNAs or activated indirectly via miRNA-mediated inhibition of its upstream suppressor (Figure 1). Therefore, a mixed miRNA pool, instead of a single miRNA, is more likely to orchestrate the regulatory network involved in thymic development and aging. Within a given miRNA pool, some miRNAs may suppress certain genes, while others may suppress inhibitory genes to indirectly turn on the suppressed/silent genes. Therefore, the complicated and intricate regulatory network in the thymus can potentially be regulated for development and rejuvenation by a mixed miRNA pool, rather than by a single miRNA.

As expected, recent studies have demonstrated the role of miRNAs in TEC biology. Cortical TECs (cTECs), immature medullary TEClow (mTEClow), and mature mTEChigh cells were used for miRNA microarray analysis, which demonstrated that the miRNA expression profile changes as the cell matures [74]. When the entire miRNA pool was abolished in TECs by conditionally deleting Dicer, which is the miRNA maturation enzyme responsible for cleaving the pre-miRNA to the miRNA duplex, the apoptosis of mTECs was induced and cTECs failed to impose efficient positive selection. Thymic cellularity was decreased in the Dicer conditional knockout mice, resulting in the inability to maintain a regular thymic microenvironment. Additionally, T cell phenotypes were altered, including reduced naive CD4+ and CD8+ T cells, and increased CD8+ effector (CD44hiCD62Llow/−) and central memory (CD44hiCD62Lhi) T cells, and T lymphopoietic activity was diminished [42, 75].

To further understand the function of canonical miRNAs in TECs, DGCR8 was specifically deleted in TECs using a Cre-LoxP system (termed Dgcr8ΔTEC) [43]. It was found that DGCR8 is critical for maintaining the proper expression of Aire and its ablation is associated with a disruption in the overall architecture of the thymic medulla. Furthermore, deficiency of the entire pool of miRNAs due to DGCR8 deletion in TECs caused a breakdown in central tolerance [43], which is normally established in the medulla through mTEC-mediated negative selection and thymic regulatory T cells (Treg) generation. The Dgcr8ΔTEC mice showed a significant loss of Aire+ mTECs, combined with an expansion of self-reactive CD4+ T cells. In addition, autoantibodies and autoimmune uveitis were generated in immunized Dgcr8ΔTEC mice when compared with littermate controls [43].

4. miRNAs Play a Role in Thymic Epithelial Cell Development and Homeostasis by Regulating Critical Transcriptional Factors

As mentioned above, FoxN1 acts as a key regulator of TEC development and differentiation in the fetal and adult thymus, and miRNAs can regulate TEC development and differentiation by directly or indirectly targeting FoxN1 gene (Figure 1). There are four reports providing evidence to confirm this point of view.

Firstly, using a miR-205fl/fl:FoxN1-Cre mice to delete miR-205 in all TECs in the thymus, Hoover group demonstrated that miR-205 plays an important role in supporting T cell development following high-dose inflammatory perturbations, because conditional ablation of miR-205 caused a severe thymic hypoplasia and delayed T cell recovery, accompanied with gene expression changes in chemokine/chemokine receptor pathways, antigen processing components, and WNT signaling system [76]. Hoover group also found that miR-205 is highly expressed in both cTECs and mTECs but is largely dispensable for thymus recovery in response to low-level inflammation [73, 77]. Compared to the miR-205fl/fl:FoxN1-Cre conditional knockout mice, FoxN1 expression levels were 2-fold higher in FoxN1-Cre mice. This expression change was also confirmed using fetal thymic organ culture prepared from E14.5 (gestation at 14.5 days) embryos from wild type and miR-205fl/fl:FoxN1-Cre mice. The results suggest that miR-205 is required for FoxN1 expression and epithelial cell function in fetal organogenesis and adult homeostasis following inflammatory perturbations [76]. Furthermore, incubation with miR-205 mimics (called agomirs) restored FoxN1 levels in the fetal thymic organ culture model. MiR-205 agomirs also increased the levels of ccl25 and stem cell factor (SCF), which are downstream targets for FoxN1. MiR-205 regulates FoxN1 levels in TECs probably by promoting the degradation of mRNAs whose products suppress FoxN1 expression (diagramed in Figure 1, indirect impact). The authors tried to assess whether 3-UTRs in any of nineteen candidate genes had 3 or more predicted miR-205 binding sites, in order to find genes that impact FoxN1 [76]. In addition to miR-205, miR-18b and miR-518b were also found to affect FoxN1 by suppressing its expression, potentially through directly targeting FoxN1 3-UTRs (diagramed in Figure 1, direct impact).

In the second approach, Kushwaha et al. performed miRNA profiling of bone morphogenetic protein-2-treated NT2/D1 cells using the Agilent Human V2 miRNA v.10.1 array and screened out two miRNAs, miR-18b and miR-518b, which directly bind to FoxN1 3-UTRs and inhibit FoxN1 expression [78]. Interfering with these two miRNAs separately or simultaneously can increase FoxN1 gene expression. When these two miRNAs were overexpressed separately or simultaneously, FoxN1 expression was downregulated. These results demonstrate that miR-18b and miR-518b are upstream controllers of FoxN1 in TECs [78]. Thirdly, miR-22 is also a posttranscriptional regulator which directly represses FoxN1 [9]. In a TRE-miR-22 mouse model (K14-rtTA/TRE-miR-22 double transgenic mice), miR-22 overexpression in the skin promoted the anagen-to-catagen transition, inhibited keratinocyte expansion and differentiation, and enhanced hair follicle apoptosis. Since hair development is regulated by multiple hair differentiation regulators, including Dlx3, Hoxc13, FoxN1, and Lef1, miR-22 potentially directly targets these genes [9]. Given that miR-22 impacts epithelial cell development in the skin and might regulate FoxN1, a logical assumption is that miR-22 is likely to control the function of thymic epithelial cells. Finally, there was a recent report in which miR125a-5p, whose expression is increased in the aged thymus, was found to negatively regulate FoxN1 expression in the aged thymus [79].

Transcription factor Trp63, a homolog of the tumor suppressor p53, is critical for the development of epithelial tissues, including the thymus [80]. The p63-FoxN1 regulatory axis has been shown to regulate postnatal TEC homeostasis in Su group’s work [10], but the study failed to identify the upstream effector responsible for regulating this axis. It has been reported that a number of miRNAs play an important role in epidermal cell proliferation and homeostasis by targeting p63 [8184], implying that these miRNAs may play a role in thymic development.

The p63 gene functions as an essential regulator of stem cell maintenance in stratified epithelial tissues and is also a target of some miRNAs. For example, miR-203 has an immediate and long-term impact on epidermal cell proliferation by directly regulating p63 [8588]. MiR-203 was reported to promote epidermal differentiation by restricting proliferative potential and inducing cell cycle exit through directly repressing p63 [88]. To support that, Jackson group used established keratinocytes from K14-rtTA/pTRE2-miR-203 double positive skin and found that miR-203 is closely correlated with the epidermal differentiation in a spatiotemporally specific manner by both immediate inhibition of cell cycle progression and long-term inhibition of stem cell self-renewal [85]. They also identified a pool of miR-203-targeted genes using a genome-wide approach. These miR-203-targeted genes, including p63, Msi2, and Skp2, play a coregulatory role that is crucial for driving cell cycle exit and restricting proliferative potential [85]. Furthermore, Chikh et al. demonstrated that the inhibitory apoptosis-stimulating protein of p53 (iASPP), a member of the apoptosis-stimulating protein of p53 (ASPP) family, represses p63 expression through miR-574-3p and miR-720. They found that iASPP is required for the homeostasis of epithelia [89]. MiR-720 and miR-574-3p were found to be upregulated as a consequence of iASPP silencing using an Agilent microRNA profiling assay. When coexpressed with a luciferase reporter gene containing the 3-UTR of human p63, both MiR-720 and miR-574-3p significantly reduced luciferase activity. Use of antagomirs for miR-574-3p and miR-720 in keratinocytes restored ΔNp63 endogenous protein levels in sh-iASPP cells. Furthermore, using antagomirs for miR-574-3p and miR-720 can both prevent the ΔNp63 downregulation typically observed during primary keratinocyte differentiation [89]. In addition, miR-130b has been reported to directly repress ΔNp63 expression in keratinocyte senescence [84].

On the other hand, p63 can regulate the expression of some miRNAs. TAp63 binds to and transactivates the Dicer promoter and suppresses metastasis through the regulation of Dicer and a number of specific miRNAs, including miR-130b [90]. ΔNp63 in epidermal cells is a transcriptional regulator of DGCR8, which localizes to the cell nucleus and is required for miRNA processing [91]. Further, p63 mediated cell cycle progression in epidermal cells by directly repressing miR-34a and miR-34c [92]. Many miRNAs, such as miR-192/215, miR-107, miR-96,132, and miR-145, are known transcriptional targets of p63 [46, 93]. Wu group has elucidated multiple p63-regulated miRNAs’ (miR-17, miR-20b, miR-30a, miR-106a, miR-143, and miR-455-3p) roles in the onset of keratinocyte differentiation [81]. It should be noted that all these experiments were conducted in skin epithelial cells, and therefore no direct evidence has been found yet to show that miRNA regulation on p63 is also engaged in thymic development and aging. Although skin epithelial cells share many similarities with TECs and these findings can provide a shortcut to study miRNA regulation in TECs, subsequent experiments in TECs are still required.

Aire gene is a transcription factor that controls expression of peripheral tissue antigen (PTA) genes in mTECs. Aire controls hundreds or even thousands of PTAs and has been proposed to function as a nonclassical TF based on the fact that the gene does not have many DNA-binding sites for direct interaction [94]. As for the regulation of Aire, specific miRNAs, such as miR-29a, in TECs play a key role. Deletion of miR-29a resulted in a progressively decreased expression of Aire and Aire-dependent genes in a miR-29a null mutant mouse model [74]. Additionally, miR-220b may act as a regulator for Aire gene translation, since mutation in miR-202R significantly reduced the level of Aire protein [95]. Although there is insufficient evidence that Aire expression is regulated by miRNAs, Aire has been shown to control 30 Aire-dependent miRNAs. Eighteen of these 30 miRNAs were upregulated, and the rest were downregulated in Aire-silenced thymic mTECs [96], strongly suggesting that these miRNAs are under the control of Aire. Therefore, Aire might function as an upstream controller of these miRNAs, which in turn, plays a potential role in the control of PTAs in mTECs [42, 74, 96, 97]. Microarray profiling of TEC subpopulations showed that series of miRNAs were significantly upregulated during terminal mTEC differentiation. For example, miR-124, miR-129, miR-202, miR-203, miR-302b, and miR-467a were expressed at two- to tenfold higher levels in the mTEChigh than in the mTEClow (expression levels were all normalized to MHC-II surface expression levels) both in mouse and human thymus. The mTEChigh population can be further divided into Aire and Aire+ subsets, and the above-mentioned miRNAs were all downregulated in Aire+mTEChigh compared to AiremTEChigh, with the exception of miR-302b, suggesting a mutual regulatory relationship between Aire and miRNAs during mTEC maturation. It was further demonstrated that miR-202 was upregulated in both immature and mature mTECs of Aire null mutants, while miR-129, miR-499, and miR-302b were significantly downregulated in mature mTECs of Aire null mutants compared to wild type mice [74]. To determine which miRNA controls PTAs in the mTECs and whether Aire expression levels could affect these interactions, Oliveira group constructed miRNA-mRNA interaction networks and found that miRNA let-7b interacted with the PTA mRNAs and confirmed the existence of a link between Aire and miRNAs in controlling the promiscuous gene expression pattern in mTECs [94].

Although the mechanism of thymic involution has not been fully understood yet, the role played by miRNAs in this process cannot be ignored [98, 99]. For example, Guo group demonstrated that miR-181a-5p expression was increased in aged TECs, which might contribute to age-related thymic involution through downregulating the phosphorylation of Smad3 and blocking the activation of the TGF-β signaling [98]. WNT signaling in thymic epithelia is essential for normal thymus development and function [100] and was suppressed in the senescent human thymus [99]. Studies compared the difference in miRNA expression between old (70-year-old men) and young (<10-month-old newborns) thymus and found that miRNAs, such as miR-25, miR-7f, and miR-134, which are known modulators of the WNT pathway, were also altered [99]. Since TEC development and homeostasis are mostly controlled by p63, FoxN1, and Aire, miRNAs associated with these genes would be potential targets of therapeutic value. Targeting miRNAs with mimics or inhibitors is a potential strategy to rejuvenate age-related declined thymic function. In one of our published reports, we found that miRNA pools from young and aged thymus have different spectrums [79]. The strategy to rejuvenate age-related declined thymic function would be to suppress upregulated miRNAs and promote downregulated miRNAs in the senescent TECs. We hypothesize that a mixed pool of miRNA is involved in the regulation of age-related thymic involution. Therefore, multiple combinations of synthesized miRNA mimics (agomirs) targeting the downregulated miRNAs and miRNA inhibitors (antagomirs) against the upregulated miRNAs are probably the best solution to restore the age-related declined thymic function.

Thymic atrophy is attributed to increased age-related chronic inflammation, and suppressing this inflammation may alleviate thymic atrophy or restore thymic function [101]. Since miRNAs also control inflammation reactions, this might provide another approach to rejuvenating age-related thymic involution. For example, miR146a was reported to suppress inflammation, miR155 was reported to promote inflammation, and the absence of miR146a [34, 102], or upregulation of miR155 [103105], promotes chronic inflammation with age. Furthermore, miR146a and miR155 counterregulate the immune response during chronic inflammation. Thus, combinational application of miR146a-agomir and miR155-antagomir might attenuate age-related atrophied thymic inflammation, thereby improving central immune tolerance generation.

6. Summary

In conclusion, miRNAs play a role in fine-tuning multiple transcription factor (TF) expression in TECs and thereby have a significant impact on thymus organogenesis, maturation, and involution at a posttranscriptional level. We reviewed recent progresses in studying the potential function of miRNAs in age-related thymic involution. Apparently, TEC development, homeostasis, and involution are very complicated processes each with a comprehensive regulatory network. Without a doubt, transcription factors p63, FoxN1, and Aire should be the primary targets for rejuvenating age-related declined thymic function. Modulation of the miRNA levels for regulating these TFs in the aged thymus via synthesized miRNA mimics (agomirs) or miRNA inhibitors (antagomirs) might provide an efficient approach for rejuvenating age-related thymic involution. Although current evidence is still insufficient for explaining how miRNAs regulate these TEC-autonomous TFs and subsequently induce thymic involution, we hope this review will help to summarize previous studies and guide future work towards discovering potential miRNA candidates for therapeutic targets.


TEC:Thymic epithelial cell
cTEC:Cortical thymic epithelial cell
mTEC:Medullary thymic epithelial cell
TF:Transcription factors
Aire:Autoimmune regulator
UTR:Untranslated region
ASPP:Apoptosis-stimulating protein of p53
iASPP:Inhibitory of ASPP
PTA:Peripheral tissue antigen.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.


This work was partially supported by grants from the Higher Education Foundation of Jiangxi Provincial (KJLD2090), the Natural Science Foundation of Jiangxi Province (20132BAB205032), and the National Natural Science Foundation of China (31260279 and 31660256) to Liefeng Wang.


  1. C. Z. Chen, L. Li, H. F. Lodish, and D. P. Bartel, “MicroRNAs modulate hematopoietic lineage differentiation,” Science, vol. 303, no. 5654, pp. 83–86, 2004. View at: Publisher Site | Google Scholar
  2. S. Kohlhaas, O. A. Garden, C. Scudamore, M. Turner, K. Okkenhaug, and E. Vigorito, “Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells,” Journal of Immunology, vol. 182, no. 5, pp. 2578–2582, 2009. View at: Publisher Site | Google Scholar
  3. S. A. Muljo, K. M. Ansel, C. Kanellopoulou, D. M. Livingston, A. Rao, and K. Rajewsky, “Aberrant T cell differentiation in the absence of Dicer,” The Journal of Experimental Medicine, vol. 202, no. 2, pp. 261–269, 2005. View at: Publisher Site | Google Scholar
  4. L. Deng, H. Liang, M. Xu et al., “STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors,” Immunity, vol. 41, no. 5, pp. 843–852, 2014. View at: Publisher Site | Google Scholar
  5. H. X. Chu, H. A. Kim, S. Lee et al., “Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 34, no. 3, pp. 450–459, 2014. View at: Publisher Site | Google Scholar
  6. K. S. Kang and J. E. Trosko, “Stem cells in toxicology: fundamental biology and practical considerations,” Toxicological Sciences, vol. 120, Supplement 1, pp. S269–S289, 2011. View at: Publisher Site | Google Scholar
  7. P. M. Garfin, D. Min, J. L. Bryson et al., “Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression,” The Journal of Experimental Medicine, vol. 210, no. 6, pp. 1087–1097, 2013. View at: Publisher Site | Google Scholar
  8. J. B. Tagne, O. R. Mohtar, J. D. Campbell et al., “Transcription factor and microRNA interactions in lung cells: an inhibitory link between NK2 homeobox 1, miR-200c and the developmental and oncogenic factors Nfib and Myb,” Respiratory Research, vol. 16, p. 22, 2015. View at: Publisher Site | Google Scholar
  9. S. Yuan, F. Li, Q. Meng et al., “Post-transcriptional regulation of keratinocyte progenitor cell expansion, differentiation and hair follicle regression by miR-22,” PLoS Genetics, vol. 11, no. 5, article e1005253, 2015. View at: Publisher Site | Google Scholar
  10. P. Burnley, M. Rahman, H. Wang et al., “Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging,” Cell Death & Disease, vol. 4, article e932, 2013. View at: Publisher Site | Google Scholar
  11. E. Candi, A. Rufini, A. Terrinoni et al., “DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 29, pp. 11999–12004, 2007. View at: Publisher Site | Google Scholar
  12. R. V. Chilukuri, V. K. Patel, M. Martinez, J. C. Guyden, and M. D. Samms, “The antigenic determinant that defines thymic nurse cells is expressed by thymic epithelial progenitor cells,” Frontiers in Cell and Development Biology, vol. 2, no. 13, 2014. View at: Publisher Site | Google Scholar
  13. R. Romano, L. Palamaro, A. Fusco et al., “FOXN1: a master regulator gene of thymic epithelial development program,” Frontiers in Immunology, vol. 4, p. 187, 2013. View at: Publisher Site | Google Scholar
  14. O. Gressner, T. Schilling, K. Lorenz et al., “TAp63alpha induces apoptosis by activating signaling via death receptors and mitochondria,” The EMBO Journal, vol. 24, no. 13, pp. 2458–2471, 2005. View at: Publisher Site | Google Scholar
  15. D. D. Taub and D. L. Longo, “Insights into thymic aging and regeneration,” Immunological Reviews, vol. 205, pp. 72–93, 2005. View at: Publisher Site | Google Scholar
  16. H. E. Lynch, G. L. Goldberg, A. Chidgey, M. R. Van den Brink, R. Boyd, and G. D. Sempowski, “Thymic involution and immune reconstitution,” Trends in Immunology, vol. 30, no. 7, pp. 366–373, 2009. View at: Publisher Site | Google Scholar
  17. J. Abramson and G. Anderson, “Thymic epithelial cells,” Annual Review of Immunology, vol. 35, pp. 85–118, 2017. View at: Publisher Site | Google Scholar
  18. D. B. Klug, C. Carter, E. Crouch, D. Roop, C. J. Conti, and E. R. Richie, “Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 20, pp. 11822–11827, 1998. View at: Publisher Site | Google Scholar
  19. W. van Ewijk, G. Hollander, C. Terhorst, and B. Wang, “Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets,” Development, vol. 127, no. 8, pp. 1583–1591, 2000. View at: Google Scholar
  20. X. Zhu, J. Gui, J. Dohkan, L. Cheng, P. F. Barnes, and D. M. Su, “Lymphohematopoietic progenitors do not have a synchronized defect with age-related thymic involution,” Aging Cell, vol. 6, no. 5, pp. 663–672, 2007. View at: Publisher Site | Google Scholar
  21. D. M. Su, D. Aw, and D. B. Palmer, “Immunosenescence: a product of the environment?” Current Opinion in Immunology, vol. 25, no. 4, pp. 498–503, 2013. View at: Publisher Site | Google Scholar
  22. B. Coder and D. M. Su, “Thymic involution beyond T-cell insufficiency,” Oncotarget, vol. 6, no. 26, pp. 21777-21778, 2015. View at: Publisher Site | Google Scholar
  23. L. Sun, J. Guo, R. Brown, T. Amagai, Y. Zhao, and D. M. Su, “Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution,” Aging Cell, vol. 9, no. 3, pp. 347–357, 2010. View at: Publisher Site | Google Scholar
  24. Y. Takahama, I. Ohigashi, S. Baik, and G. Anderson, “Generation of diversity in thymic epithelial cells,” Nature Reviews Immunology, vol. 17, no. 5, pp. 295–305, 2017. View at: Publisher Site | Google Scholar
  25. M. Itoi, H. Kawamoto, Y. Katsura, and T. Amagai, “Two distinct steps of immigration of hematopoietic progenitors into the early thymus anlage,” International Immunology, vol. 13, no. 9, pp. 1203–1211, 2001. View at: Publisher Site | Google Scholar
  26. C. Chen, Y. Liu, and P. Zheng, “mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells,” Science Signaling, vol. 2, no. 98, article ra75, 2009. View at: Publisher Site | Google Scholar
  27. M. Nehls, K. Luno, M. Schorpp et al., “A yeast artificial chromosome contig on mouse chromosome 11 encompassing the nu locus,” European Journal of Immunology, vol. 24, no. 7, pp. 1721–1723, 1994. View at: Publisher Site | Google Scholar
  28. D. Lee, D. M. Prowse, and J. L. Brissette, “Association between mouse nude gene expression and the initiation of epithelial terminal differentiation,” Developmental Biology, vol. 208, no. 2, pp. 362–374, 1999. View at: Publisher Site | Google Scholar
  29. L. Cheng, J. Guo, L. Sun et al., “Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy,” The Journal of Biological Chemistry, vol. 285, no. 8, pp. 5836–5847, 2010. View at: Publisher Site | Google Scholar
  30. L. Chen, S. Xiao, and N. R. Manley, “Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner,” Blood, vol. 113, no. 3, pp. 567–574, 2009. View at: Publisher Site | Google Scholar
  31. A. S. Adler, T. L. Kawahara, E. Segal, and H. Y. Chang, “Reversal of aging by NFkappaB blockade,” Cell Cycle, vol. 7, no. 5, pp. 556–559, 2008. View at: Publisher Site | Google Scholar
  32. M. Senoo, F. Pinto, C. P. Crum, and F. McKeon, “p63 is essential for the proliferative potential of stem cells in stratified epithelia,” Cell, vol. 129, no. 3, pp. 523–536, 2007. View at: Publisher Site | Google Scholar
  33. D. M. Su, S. Navarre, W. J. Oh, B. G. Condie, and N. R. Manley, “A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation,” Nature Immunology, vol. 4, no. 11, pp. 1128–1135, 2003. View at: Publisher Site | Google Scholar
  34. M. P. Boldin, K. D. Taganov, D. S. Rao et al., “miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice,” The Journal of Experimental Medicine, vol. 208, no. 6, pp. 1189–1201, 2011. View at: Publisher Site | Google Scholar
  35. T. Corbeaux, I. Hess, J. B. Swann, B. Kanzler, A. Haas-Assenbaum, and T. Boehm, “Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 38, pp. 16613–16618, 2010. View at: Publisher Site | Google Scholar
  36. J. Xia, H. Wang, J. Guo, Z. Zhang, B. Coder, and D. M. Su, “Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection,” Aging Dis, vol. 3, no. 3, pp. 248–259, 2012. View at: Google Scholar
  37. B. D. Coder, H. Wang, L. Ruan, and D. M. Su, “Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation,” Journal of Immunology, vol. 194, no. 12, pp. 5825–5837, 2015. View at: Publisher Site | Google Scholar
  38. G. O. Gillard, J. Dooley, M. Erickson, L. Peltonen, and A. G. Farr, “Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation,” Journal of Immunology, vol. 178, no. 5, pp. 3007–3015, 2007. View at: Publisher Site | Google Scholar
  39. M. S. Anderson, E. S. Venanzi, L. Klein et al., “Projection of an immunological self shadow within the thymus by the aire protein,” Science, vol. 298, no. 5597, pp. 1395–1401, 2002. View at: Publisher Site | Google Scholar
  40. M. Meredith, D. Zemmour, D. Mathis, and C. Benoist, “Aire controls gene expression in the thymic epithelium with ordered stochasticity,” Nature Immunology, vol. 16, no. 9, pp. 942–949, 2015. View at: Publisher Site | Google Scholar
  41. Y. Herzig, S. Nevo, C. Bornstein et al., “Transcriptional programs that control expression of the autoimmune regulator gene Aire,” Nature Immunology, vol. 18, no. 2, pp. 161–172, 2017. View at: Publisher Site | Google Scholar
  42. A. S. Papadopoulou, J. Dooley, M. A. Linterman et al., “The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-alpha receptor,” Nature Immunology, vol. 13, no. 2, pp. 181–187, 2011. View at: Publisher Site | Google Scholar
  43. I. S. Khan, R. T. Taniguchi, K. J. Fasano, M. S. Anderson, and L. T. Jeker, “Canonical microRNAs in thymic epithelial cells promote central tolerance,” European Journal of Immunology, vol. 44, no. 5, pp. 1313–1319, 2014. View at: Publisher Site | Google Scholar
  44. G. A. Passos, D. A. Mendes-da-Cruz, and E. H. Oliveira, “The thymic orchestration involving Aire, miRNAs, and cell-cell interactions during the induction of central tolerance,” Frontiers in Immunology, vol. 6, p. 352, 2015. View at: Publisher Site | Google Scholar
  45. J. Gordon, A. R. Bennett, C. C. Blackburn, and N. R. Manley, “Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch,” Mechanisms of Development, vol. 103, no. 1-2, pp. 141–143, 2001. View at: Publisher Site | Google Scholar
  46. L. Boominathan, “The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex,” PLoS One, vol. 5, no. 5, article e10615, 2010. View at: Publisher Site | Google Scholar
  47. D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004. View at: Google Scholar
  48. G. Pepin and M. P. Gantier, “microRNA decay: refining microRNA regulatory activity,” MicroRNA, vol. 5, no. 3, pp. 167–174, 2016. View at: Publisher Site | Google Scholar
  49. V. Ambros, “The functions of animal microRNAs,” Nature, vol. 431, no. 7006, pp. 350–355, 2004. View at: Publisher Site | Google Scholar
  50. J. W. Leong, R. P. Sullivan, and T. A. Fehniger, “microRNA management of NK-cell developmental and functional programs,” European Journal of Immunology, vol. 44, no. 10, pp. 2862–2868, 2014. View at: Publisher Site | Google Scholar
  51. H. Zhang, K. L. Artiles, and A. Z. Fire, “Functional relevance of “seed” and “non-seed” sequences in microRNA-mediated promotion of C. elegans developmental progression,” RNA, vol. 21, no. 11, pp. 1980–1992, 2015. View at: Publisher Site | Google Scholar
  52. L. Constantin, M. Constantin, and B. J. Wainwright, “MicroRNA biogenesis and hedgehog-patched signaling cooperate to regulate an important developmental transition in granule cell development,” Genetics, vol. 202, no. 3, pp. 1105–1118, 2016. View at: Publisher Site | Google Scholar
  53. S. Chen, Z. Wang, X. Dai et al., “Re-expression of microRNA-150 induces EBV-positive Burkitt lymphoma differentiation by modulating c-Myb in vitro,” Cancer Science, vol. 104, no. 7, pp. 826–834, 2013. View at: Publisher Site | Google Scholar
  54. T. Chen, A. Margariti, S. Kelaini et al., “MicroRNA-199b modulates vascular cell fate during iPS cell differentiation by targeting the notch ligand Jagged1 and enhancing VEGF signaling,” Stem Cells, vol. 33, no. 5, pp. 1405–1418, 2015. View at: Publisher Site | Google Scholar
  55. R. W. Georgantas 3rd, R. Hildreth, S. Morisot et al., “CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 8, pp. 2750–2755, 2007. View at: Publisher Site | Google Scholar
  56. N. Mobarra, A. Shafiee, S. M. Rad et al., “Overexpression of microRNA-16 declines cellular growth, proliferation and induces apoptosis in human breast cancer cells,” In Vitro Cellular & Developmental Biology. Animal, vol. 51, no. 6, pp. 604–611, 2015. View at: Publisher Site | Google Scholar
  57. Y. Li, D. Chen, L. Jin et al., “MicroRNA-20b-5p functions as a tumor suppressor in renal cell carcinoma by regulating cellular proliferation, migration and apoptosis,” Molecular Medicine Reports, vol. 13, no. 2, pp. 1895–1901, 2016. View at: Publisher Site | Google Scholar
  58. Y. Li, D. Chen, L. U. Jin et al., “Oncogenic microRNA-142-3p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma,” Oncology Letters, vol. 11, no. 2, pp. 1235–1241, 2016. View at: Publisher Site | Google Scholar
  59. D. Lenkala, B. LaCroix, E. R. Gamazon, P. Geeleher, H. K. Im, and R. S. Huang, “The impact of microRNA expression on cellular proliferation,” Human Genetics, vol. 133, no. 7, pp. 931–938, 2014. View at: Publisher Site | Google Scholar
  60. L. F. Xu, Z. P. Wu, Y. Chen, Q. S. Zhu, S. Hamidi, and R. Navab, “MicroRNA-21 (miR-21) regulates cellular proliferation, invasion, migration, and apoptosis by targeting PTEN, RECK and Bcl-2 in lung squamous carcinoma, Gejiu City, China,” PLoS One, vol. 9, no. 8, article e103698, 2014. View at: Publisher Site | Google Scholar
  61. P. Xu, S. Y. Vernooy, M. Guo, and B. A. Hay, “The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism,” Current Biology, vol. 13, no. 9, pp. 790–795, 2003. View at: Publisher Site | Google Scholar
  62. A. Meerson, M. Traurig, V. Ossowski, J. M. Fleming, M. Mullins, and L. J. Baier, “Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNF-α,” Diabetologia, vol. 56, no. 9, pp. 1971–9, 2013. View at: Publisher Site | Google Scholar
  63. R. O. Benatti, A. M. Melo, F. O. Borges et al., “Maternal high-fat diet consumption modulates hepatic lipid metabolism and microRNA-122 (miR-122) and microRNA-370 (miR-370) expression in offspring,” The British Journal of Nutrition, vol. 111, no. 12, pp. 2112–2122, 2014. View at: Publisher Site | Google Scholar
  64. R. J. Johnston and O. Hobert, “A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans,” Nature, vol. 426, no. 6968, pp. 845–849, 2003. View at: Publisher Site | Google Scholar
  65. Y. W. Hsieh, C. Chang, and C. F. Chuang, “The microRNA mir-71 inhibits calcium signaling by targeting the TIR-1/Sarm1 adaptor protein to control stochastic L/R neuronal asymmetry in C. elegans,” PLoS Genetics, vol. 8, no. 8, article e1002864, 2012. View at: Publisher Site | Google Scholar
  66. S. Chang, R. J. Johnston Jr., C. Frokjaer-Jensen, S. Lockery, and O. Hobert, “MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode,” Nature, vol. 430, no. 7001, pp. 785–789, 2004. View at: Publisher Site | Google Scholar
  67. L. Sun, Q. Wang, X. Gao, D. Shi, S. Mi, and Q. Han, “MicroRNA-454 functions as an oncogene by regulating PTEN in uveal melanoma,” FEBS Letters, vol. 589, no. 19 Part B, pp. 2791–2796, 2015. View at: Publisher Site | Google Scholar
  68. C. J. Krause, O. Popp, N. Thirunarayanan, G. Dittmar, M. Lipp, and G. Muller, “MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR,” Oncotarget, vol. 7, no. 9, pp. 10414–10432, 2016. View at: Publisher Site | Google Scholar
  69. M. J. Bueno, I. Pérez de Castro, M. Gómez de Cedrón et al., “Genetic and epigenetic silencing of MicroRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression,” Cancer Cell, vol. 29, no. 4, pp. 607-608, 2016. View at: Publisher Site | Google Scholar
  70. I. Fukumoto, K. Koshizuka, T. Hanazawa et al., “The tumor-suppressive microRNA-23b/27b cluster regulates the MET oncogene in oral squamous cell carcinoma,” International Journal of Oncology, vol. 49, no. 3, pp. 1119–1129, 2016. View at: Publisher Site | Google Scholar
  71. J. Lu, G. Getz, E. A. Miska et al., “MicroRNA expression profiles classify human cancers,” Nature, vol. 435, no. 7043, pp. 834–838, 2005. View at: Publisher Site | Google Scholar
  72. B. J. Reinhart, F. J. Slack, M. Basson et al., “The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans,” Nature, vol. 403, no. 6772, pp. 901–906, 2000. View at: Publisher Site | Google Scholar
  73. I. S. Khan, C. Y. Park, A. Mavropoulos et al., “Identification of MiR-205 as a microRNA that is highly expressed in medullary thymic epithelial cells,” PLoS One, vol. 10, no. 8, article e0135440, 2015. View at: Publisher Site | Google Scholar
  74. O. Ucar, L. O. Tykocinski, J. Dooley, A. Liston, and B. Kyewski, “An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression,” European Journal of Immunology, vol. 43, no. 7, pp. 1769–1778, 2013. View at: Publisher Site | Google Scholar
  75. S. Zuklys, C. E. Mayer, S. Zhanybekova et al., “MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection,” Journal of Immunology, vol. 189, no. 8, pp. 3894–3904, 2012. View at: Publisher Site | Google Scholar
  76. A. R. Hoover, I. Dozmorov, J. MacLeod et al., “MicroRNA-205 maintains T cell development following stress by regulating forkhead box N1 and selected chemokines,” The Journal of Biological Chemistry, vol. 291, no. 44, pp. 23237–23247, 2016. View at: Publisher Site | Google Scholar
  77. S. Belkaya, R. L. Silge, A. R. Hoover et al., “Dynamic modulation of thymic microRNAs in response to stress,” PLoS One, vol. 6, no. 11, article e27580, 2011. View at: Publisher Site | Google Scholar
  78. R. Kushwaha, V. Thodima, M. J. Tomishima, G. J. Bosl, and R. S. Chaganti, “miR-18b and miR-518b target FOXN1 during epithelial lineage differentiation in pluripotent cells,” Stem Cells and Development, vol. 23, no. 10, pp. 1149–1156, 2014. View at: Publisher Site | Google Scholar
  79. M. Xu, O. Sizova, L. Wang, and D. M. Su, “A fine-tune role of mir-125a-5p on Foxn1 during age-associated changes in the thymus,” Aging and Disease, vol. 8, no. 3, pp. 277–286, 2017. View at: Publisher Site | Google Scholar
  80. C. P. Crum and F. D. McKeon, “p63 in epithelial survival, germ cell surveillance, and neoplasia,” Annual Review of Pathology, vol. 5, pp. 349–371, 2010. View at: Publisher Site | Google Scholar
  81. N. Wu, E. Sulpice, P. Obeid et al., “The miR-17 family links p63 protein to MAPK signaling to promote the onset of human keratinocyte differentiation,” PLoS One, vol. 7, no. 9, article e45761, 2012. View at: Publisher Site | Google Scholar
  82. T. Wei, K. Orfanidis, N. Xu et al., “The expression of microRNA-203 during human skin morphogenesis,” Experimental Dermatology, vol. 19, no. 9, pp. 854–856, 2010. View at: Publisher Site | Google Scholar
  83. A. J. Stacy, M. P. Craig, S. Sakaram, and M. Kadakia, “DeltaNp63alpha and microRNAs: leveraging the epithelial-mesenchymal transition,” Oncotarget, vol. 8, no. 2, pp. 2114–2129, 2017. View at: Publisher Site | Google Scholar
  84. P. Rivetti di Val Cervo, A. M. Lena, M. Nicoloso et al., “p63-microRNA feedback in keratinocyte senescence,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 4, pp. 1133–1138, 2012. View at: Publisher Site | Google Scholar
  85. S. J. Jackson, Z. Zhang, D. Feng et al., “Rapid and widespread suppression of self-renewal by microRNA-203 during epidermal differentiation,” Development, vol. 140, no. 9, pp. 1882–1891, 2013. View at: Publisher Site | Google Scholar
  86. A. M. Lena, R. Shalom-Feuerstein, P. Rivetti di Val Cervo et al., “miR-203 represses ‘stemness’ by repressing DeltaNp63,” Cell Death and Differentiation, vol. 15, no. 7, pp. 1187–1195, 2008. View at: Publisher Site | Google Scholar
  87. U. A. Orom, M. K. Lim, J. E. Savage et al., “MicroRNA-203 regulates caveolin-1 in breast tissue during caloric restriction,” Cell Cycle, vol. 11, no. 7, pp. 1291–1295, 2012. View at: Publisher Site | Google Scholar
  88. R. Yi, M. N. Poy, M. Stoffel, and E. Fuchs, “A skin microRNA promotes differentiation by repressing ‘stemness’,” Nature, vol. 452, no. 7184, pp. 225–229, 2008. View at: Publisher Site | Google Scholar
  89. A. Chikh, R. N. Matin, V. Senatore et al., “iASPP/p63 autoregulatory feedback loop is required for the homeostasis of stratified epithelia,” The EMBO Journal, vol. 30, no. 20, pp. 4261–4273, 2011. View at: Publisher Site | Google Scholar
  90. X. Su, D. Chakravarti, M. S. Cho et al., “TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs,” Nature, vol. 467, no. 7318, pp. 986–990, 2010. View at: Publisher Site | Google Scholar
  91. D. Chakravarti, X. Su, M. S. Cho et al., “Induced multipotency in adult keratinocytes through down-regulation of DeltaNp63 or DGCR8,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 5, pp. E572–E581, 2014. View at: Publisher Site | Google Scholar
  92. D. Antonini, M. T. Russo, L. De Rosa, M. Gorrese, L. Del Vecchio, and C. Missero, “Transcriptional repression of miR-34 family contributes to p63-mediated cell cycle progression in epidermal cells,” The Journal of Investigative Dermatology, vol. 130, no. 5, pp. 1249–1257, 2010. View at: Publisher Site | Google Scholar
  93. L. Boominathan, “The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network,” Cancer Metastasis Reviews, vol. 29, no. 4, pp. 613–639, 2010. View at: Publisher Site | Google Scholar
  94. E. H. Oliveira, C. Macedo, C. V. Collares et al., “Aire downregulation is associated with changes in the posttranscriptional control of peripheral tissue antigens in medullary thymic epithelial cells,” Frontiers in Immunology, vol. 7, p. 526, 2016. View at: Publisher Site | Google Scholar
  95. T. Matsuo, Y. Noguchi, M. Shindo et al., “Regulation of human autoimmune regulator (AIRE) gene translation by miR-220b,” Gene, vol. 530, no. 1, pp. 19–25, 2013. View at: Publisher Site | Google Scholar
  96. C. Macedo, A. F. Evangelista, M. M. Marques et al., “Autoimmune regulator (Aire) controls the expression of microRNAs in medullary thymic epithelial cells,” Immunobiology, vol. 218, no. 4, pp. 554–560, 2013. View at: Publisher Site | Google Scholar
  97. G. A. Passos, D. A. Mendes-da-Cruz, and E. H. Oliveira, “Editorial: the role of Aire, microRNAs and cell-cell interactions on thymic architecture and induction of tolerance,” Frontiers in Immunology, vol. 6, p. 615, 2015. View at: Publisher Site | Google Scholar
  98. D. Guo, Y. Ye, J. Qi et al., “MicroRNA-181a-5p enhances cell proliferation in medullary thymic epithelial cells via regulating TGF-β signaling,” Acta Biochimica Biophysica Sinica (Shanghai), vol. 48, no. 9, pp. 840–849, 2016. View at: Publisher Site | Google Scholar
  99. S. Ferrando-Martinez, E. Ruiz-Mateos, J. A. Dudakov et al., “WNT signaling suppression in the senescent human thymus,” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, vol. 70, no. 3, pp. 273–281, 2015. View at: Publisher Site | Google Scholar
  100. S. Zuklys, J. Gill, M. P. Keller et al., “Stabilized beta-catenin in thymic epithelial cells blocks thymus development and function,” Journal of Immunology, vol. 182, no. 5, pp. 2997–3007, 2009. View at: Publisher Site | Google Scholar
  101. G. D. Sempowski, L. P. Hale, J. S. Sundy et al., “Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy,” Journal of Immunology, vol. 164, no. 4, pp. 2180–2187, 2000. View at: Publisher Site | Google Scholar
  102. J. L. Zhao, D. S. Rao, M. P. Boldin, K. D. Taganov, R. M. O'Connell, and D. Baltimore, “NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 22, pp. 9184–9189, 2011. View at: Publisher Site | Google Scholar
  103. R. M. O'Connell, D. Kahn, W. S. Gibson et al., “MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development,” Immunity, vol. 33, no. 4, pp. 607–619, 2010. View at: Publisher Site | Google Scholar
  104. R. Hu, D. A. Kagele, T. B. Huffaker et al., “miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation,” Immunity, vol. 41, no. 4, pp. 605–619, 2014. View at: Publisher Site | Google Scholar
  105. M. Nazari-Jahantigh, Y. Wei, H. Noels et al., “MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages,” The Journal of Clinical Investigation, vol. 122, no. 11, pp. 4190–4202, 2012. View at: Publisher Site | Google Scholar

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