Epigenetic Regulation in Mesenchymal Stem Cell Aging and Differentiation and Osteoporosis

Table 2

Histone modification in MSC aging and related diseases.

Epigenetic changes	Factors	Mechanism	In vivo or in vitro	Consequence	Material	Ref.
Senescence and aging
Histone acetylation	HDAC↓	Directly upregulates JMJD3 and indirectly downregulates PcGs through RB/E2F pathway to inhibit H3K27me3 at p16^INK4A	In vitro	Aging	hADSCs, hUCSCs	[38]
Histone acetylation	HDAC↓	Promotes the transcription of p21^CIP1/WAF1 through increasing H3 and H4 acetylation	In vitro	Aging: decreased differentiation ability and proliferation rate	hADSCs, hUCSCs	[40]
Histone acetylation	SIRT6↓	Insufficient SIRT6 causes increased H3K56ac and compromised recruitment of RNAP II complex to Hmox-1 gene promoter, leading to decrease in Hmox-1 expression and impaired cellular redox homeostasis	Both	Senescence, dysregulated redox metabolism, and increased sensitivity to oxidative stress	Human embryoid bodies MSC, mouse model	[42]
Histone methylation	TWIST1↓	Insufficient to prevent senescence by recruiting EZH2 and form repressive H3K27me3 at p16/p14 promoters; upregulates E47 that binds to p16 promoter and promotes transcription activity	In vitro	Senescence	hBMSCs	[39]
Histone methylation	BMI1↓	Fails to recruit and stabilize PRC2 which protects H3K27me3 of p16^INK4A	In vitro	Aging	hADSCs, hUSCSs	[38]
Histone methylation	EZH2↓	Fails to methylate H3K27 as catalytic subunit of PRC2; insufficient H3K27me3 cannot suppress p16 and p14 expression	In vitro	Aging	hADSCs, hUSCSs	[38]
Histone methylation	G9a↓	(Unclear)	In vitro	Aging: decreased differentiation ability and proliferation rate	Rat BMSCs	[149]
Skeletal diseases
Histone methylation	EZH2↑	Promotes H3K27me3 on Wnt1, Wnt6, and Wnt10a promoters to silence Wnt signaling pathway	Both	Osteoporosis	hBMSCs, mouse BMSCs, mouse model	[47]
Histone methylation	KDM5A↑	Increases H3K4me3 levels on promoters of Runx2	Both	Osteoporosis	hBMSCs, mouse BMSCs, mouse model	[45]
Histone methylation	ASH1L↓	Fails to mediate H3K4me3 recruitment at the transcription start sites of Osx, Runx2, Sox9, and Creb genes	Both	Osteoporosis	hBMSCs, mouse BMSCs, mouse model	[46]
Histone methylation	KDM2B↓	Unable to be recruited to the promoter of AP-2α and inhibit AP-2α expression via removing H3K4me3	Both	Oculofaciocardiodental (OFCD) syndrome	hBMSCs, mouse BMSCs, mouse model	[51]
Histone acetylation	GCN5 (KAT2A)↓	Insufficient to increase H3K9 acetylation on the promoters of Wnt genes	Both	Osteoporosis	hBMSCs, mouse BMSCs, mouse model	[48]
Histone acetylation	PCAF (KAT2B)↓	Insufficient to acetylate H3K9 at promoters of BMP2, BMP4, BMPR2B, and Runx2	Both	Osteoporosis	hBMSCs, mouse BMSCs, mouse model	[49]