KDM4A regulates myogenesis by demethylating H3K9me3 of myogenic regulatory factors

Abstract

Histone lysine demethylase 4A (KDM4A) plays a crucial role in regulating cell proliferation, cell differentiation, development and tumorigenesis. However, little is known about the function of KDM4A in muscle development and regeneration. Here, we found that the conditional ablation of KDM4A in skeletal muscle caused impairment of embryonic and postnatal muscle formation. The loss of KDM4A in satellite cells led to defective muscle regeneration and blocked the proliferation and differentiation of satellite cells. Myogenic differentiation and myotube formation in KDM4A-deficient myoblasts were inhibited. Chromatin immunoprecipitation assay revealed that KDM4A promoted myogenesis by removing the histone methylation mark H3K9me3 at MyoD, MyoG and Myf5 locus. Furthermore, inactivation of KDM4A in myoblasts suppressed myoblast differentiation and accelerated H3K9me3 level. Knockdown of KDM4A in vitro reduced myoblast proliferation through enhancing the expression of the cyclin-dependent kinase inhibitor P21 and decreasing the expression of cell cycle regulator Cyclin D1. Together, our findings identify KDM4A as an important regulator for skeletal muscle development and regeneration, orchestrating myogenic cell proliferation and differentiation.

Protein arginine methyltransferase PRMT1 promotes adipogenesis by modulating transcription factors C/EBPβ and PPARγ

“…Chromatin immunoprecipitation assay was performed as described previously ( 44 ). Briefly, cells were crosslinked with 1% formaldehyde for 10 min at RT and quenched for 5 min by adding 0.125 M glycine.…”

Hypoxia Enhances HIF1α Transcription Activity by Upregulating KDM4A and Mediating H3K9me3, Thus Inducing Ferroptosis Resistance in Cervical Cancer Cells

“…KDM4A and HIF1 α were downregulated whereas H3K9me3 was upregulated in SiHa and Hela cells after transfection with shKDM4A. KDM4A inactivation stimulates the H3K9me3 level [ 47 ]. Besides, H3K9me3 was accumulated at the HIF1 α promoter after silencing KDM4A.…”

Epigenetic Control of Muscle Stem Cells: Focus on Histone Lysine Demethylases

“…(B) Upon MuSCs activation and proliferation, KDM4A is enriched on Myf5 promoter in proliferating myoblasts, where it removes H3K9me3 histone mark allowing the transcription of Myf5 and promoting cell proliferation. Conversely, KDM4A ablation results in H3K9me3 accumulation repressing the transcription ( Zhu et al, 2021 ). (C) KDM2B acts on Acta1 promoter demethylating serum response factor (SRF) and preventing its binding at serum regulatory elements (SRE), thus leading to skeletal muscle differentiation impairment.…”

“…(E) During skeletal muscle differentiation, KDM4A/B remove both H3K9me2 and H3K9me3 marks on MyoD and MyoG promoters to ensure their transcription. Thus, inhibition of KDM4A/B results into inhibition of MyoD and MyoG transcription thus skeletal muscle differentiation impairment ( Verrier et al, 2011 ; Choi et al, 2015 ; Zhu et al, 2021 ). (F) SIX4 transcriptional factor recruits UTX on Myogenin and Ckm regulatory regions, here, the histone chaperone SPT6 tethers UTX to the elongated RNApolII, in order to promote H3K27me3 demethylation all along the gene sequences.…”

“…Recently, conditional inactivation of KDM4A in MuSCs using a Myf5 -CRE driver confirmed the essential role of KDM4A for myogenesis during embryogenesis and in adult upon muscle injury. In the absence of KDM4A, damaged muscles display less differentiating (PAX7+/MYOD+) cells and proliferating (PAX7+/Ki67+) myoblasts and regeneration is impaired ( Verrier et al, 2011 ; Zhu et al, 2021 ). Mechanistically, ChIP experiments revealed that in proliferating myoblasts KDM4A is enriched on the Myf5 promoter where it removes H3K9me3, which leads to Cyclin D1 expression, thus promoting cell proliferation ( Zhu et al, 2021 ) ( Figure 2B ).…”