SRF is a nonhistone methylation target of KDM2B and SET7 in the regulation of skeletal muscle differentiation

Abstract

The demethylation of histone lysine residues, one of the most important modifications in transcriptional regulation, is associated with various physiological states. KDM2B is a demethylase of histones H3K4, H3K36, and H3K79 and is associated with the repression of transcription. Here, we present a novel mechanism by which KDM2B demethylates serum response factor (SRF) K165 to negatively regulate muscle differentiation, which is counteracted by the histone methyltransferase SET7. We show that KDM2B inhibited skeletal muscle differentiation by inhibiting the transcription of SRF-dependent genes. Both KDM2B and SET7 regulated the balance of SRF K165 methylation. SRF K165 methylation was required for the transcriptional activation of SRF and for the promoter occupancy of SRF-dependent genes. SET7 inhibitors blocked muscle cell differentiation. Taken together, these data indicate that SRF is a nonhistone target of KDM2B and that the methylation balance of SRF as maintained by KDM2B and SET7 plays an important role in muscle cell differentiation.

Population structure and genomic footprints of selection in five major Iranian horse breeds

“…For example, increased muscle glycogen and muscle fiber hypertrophy are two important phenomena of muscular adaptations to training that can affect strength and stamina of endurance horses respectively (Rivero, 2007). Interestingly, our results highlighted eight genes—ATPase sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2 ( ATP2A2 ), mitogen‐activated protein kinase 10 ( MAPK10 ), protein kinase AMP‐activated non‐catalytic subunit gamma 2 ( PRKAG2 ), myoferlin ( MYOF ), glutamate decarboxylase like 1 ( GADL1 ), lysine demethylase 2B ( KDM2B ), growth arrest specific 2 ( GAS2 ), and calcium voltage‐gated channel subunit α1 A ( CACNA1A )—as genes participating in muscle contraction (Ropka‐Molik et al, 2017), equine skeletal muscle adaptations to exercise (Bryan et al, 2017), muscular glycogenosis (Laforêt et al, 2006), muscle dystrophy regulation (Davis et al, 2000), regulation of muscle strength (Mahootchi et al, 2020), skeletal muscle differentiation (Kwon et al, 2021), muscle synthesis (Hu et al, 2021), and regulation of muscular hypotonia (Reinson et al, 2016) respectively. However, McQueen et al (2014) also revealed the contribution of an SNP (rs68536711) located in the equine MYOF gene in foals Rhodococcus equi infection susceptibility.…”

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

“…However, their physiological role in normal condition is still poorly understood. So far, only the role of KDM2B have been studied in skeletal muscle, although KDM2B its absent in adult skeletal muscle ( Kwon et al, 2021 ). KDM2B is highly expressed in muscle during late embryonic development and constantly decreases in skeletal muscle tissue with the age, supporting the idea that KDM2B needs to be silenced to achieve muscle differentiation.…”

“…Interestingly, ChIP experiments performed in myoblasts overexpressing KDM2B, revealed that H3K4me3 levels were not altered on muscle specific promoters. Mechanistically, KDM2B seems to act through the serum response factor (SRF) since it was shown to demethylate SRF, thus preventing its binding to the serum response elements (SRE) present in the promoters of muscle specific genes ( Kwon et al, 2021 ) ( Table 1 , Figure 2C ).…”

“…(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. On the contrary, KDM2B absence allows SFR to bind SRE thus resulting in Acta one transcription ( Kwon et al, 2021 ). (D) KDM3C demethylates H3K9me2 on the MyoD distal regulatory region (DRR).…”

A GSK3-SRF Axis Mediates Angiotensin II Induced Endothelin Transcription in Vascular Endothelial Cells

“… Matsuzaki et al (2003) , for instance, have discovered that lysine residue 147 of SRF can be SUMOylated, which suppresses its transcriptional activity likely by interfering with its DNA binding potential. More recently, Kwon et al (2021) have reported that lysine residue 165 of SRF can be methylated by SET7 and de-methylated by KDM2B; dynamic SRF methylation is proposed to regulate its affinity for target promotes and contribute to muscle differentiation. By far, phosphorylation represents the most extensively characterized PTM for SRF.…”