Integration of Signaling Pathways with the Epigenetic Machinery in the Maintenance of Stem Cells

Table 1

Summary of different mechanisms of signaling to chromatin.

Mechanism of signaling to chromatin	Signaling pathway	Chromatin target	Functional outcome	Reference
Histone posttranslational modifications	Serum stimulated PIM1 kinase cascade	H3S10 phosphorylation	Recruitment of MOF, which acetylates H4, thus in turn recruiting the BRD4/P-TEFb complex and stimulating transcription elongation	[14]
	Epidermal growth factor (EGF) induced Rsk2 kinase signaling	H3S10 phosphorylation	Recruitment of HAT complexes and rapid acetylation of phosphorylated H3S10	[20]
	Mitogen- and stress-induced; MSK1/2 cascade	H3S10 and S28 phosphorylation	Reduced efficiency in inducing mitogen- and stress-induced IE genes	[20]
	Cytokine stimulated IKKa kinase cascade	H3S10; phosphorylation	Regulation of NF-B-dependent gene expression after cytokine exposure	[22]
	Mitotic Aurora B kinase signaling	H3S10; phosphorylation	Displacement of HP1 from mitotic heterochromatin and gene activation	[23]
	Androgen dependent PKCβ kinase signaling	H3T6 phosphorylation	Androgen-stimulated gene expression activation, through modulation of LSD1 demethylating activity	[25]
	Epidermal growth factor (EGF) activated PKM2 kinase cascade	H3T11 phosphorylation	Dissociation of HDAC3 from CCND1 and MYC promoters, introduction of H3K9ac, and induction of transcription activation	[26]
	Jak2/STAT5 signaling pathway	H3Y41 phosphorylation	Jak2 acts as histone tyrosine kinase, which phosphorylates H3Y41 and excludes HP1a from chromatin	[38]
Modulation of nucleosome occupancy	Progesterone-activated ERK1/2 signaling	Histones H1 and H2A/H2B	ERK1/2 mediated phosphorylation of the progesterone-receptors, MSK1 and H3S10, which recruit chromatin remodeling complexes leading to the displacement of H1 and H2A/H2B and transcriptional activation of progesterone responsive genes	[33–35]
	Androgen signaling pathway	Nucleosomes	Induction of a nucleosome-depleted state at androgen receptor enhancers, leading to recruitment of histone modifiers, chromatin remodelers, and ultimately gene activation	[66]
	Hippo signaling pathway	Histones H3	The YAP/TAZ/TEAD ternary complex recruits NuRD complex on target genes, leading to histones deacetylation, increased H3 histone occupancy and reduction of chromatin accessibility	[37]
Regulation of chromatin modifiers	Stress-activated p38 kinase cascade	EZH2 Thr372 phosphorylation	PRC2-mediated repression of Pax7 during regeneration	[41]
	PI3K-AKT signaling pathway	EZH2 Ser21 phosphorylation	Suppression of EZH2 methyltransferase activity by reducing its binding to histone H3 and derepression of silenced genes	[42]
	p38 MAPK signaling pathway	MLL complexes	The signaling cascade leads to phosphorylation of Mef2d, which interacts with MLL complex, targeting it to specific genes that are activated during myogenesis	[43]