Histone Methyltransferase SETD3 Regulates Muscle Differentiation

Abstract

Histone lysine methylation, as one of the most important factors in transcriptional regulation, is associated with a various physiological conditions. Using a bioinformatics search, we identified and subsequently cloned mouse SET domain containing 3 (SETD3) with SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) and Rubis-subs-bind domains. SETD3 is a novel histone H3K4 and H3K36 methyltransferase with transcriptional activation activity. SETD3 is expressed abundantly in muscular tissues and, when overexpressed, activates transcription of muscle-related genes, myogenin, muscle creatine kinase (MCK), and myogenic factor 6 (Myf6), thereby inducing muscle cell differentiation. Conversely, knockdown of SETD3 by shRNA significantly retards muscle cell differentiation. In this study, SETD3 was recruited to the myogenin gene promoter along with MyoD where it activated transcription. Together, these data indicate that SETD3 is a H3K4/K36 methyltransferase and plays an important role in the transcriptional regulation of muscle cell differentiation.The conformational structure or molecular charge of the histone core complex can be modified via methylation of the lysine/arginine residue in the histone tail, which affects gene expression and heterochromatin formation (1). Arginine methylation is mediated by PRDM family proteins, which are characterized by the presence of a PR (PRD1-BF1 and RIZ homology) domain at their N terminus, whereas lysine is methylated by histone methyltransferase (HMTase), 4 which commonly harbors the SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) domain (2). By forming complexes with a broad variety of transcription factors, HMTases perform an important role in the regulation of gene expression, stem cell renewal, reproductive organ maturation, and tumorigenesis in mammals (2-5).Additionally, HMTases have been confirmed as crucial to myofibril organization (6), intestinal and pancreatic differentiation (7), and neurogenesis (8) in zebrafish.Muscle differentiation requires sequences of harmonized steps after the commitment of mesodermal progenitor cells to the muscular lineage (9). Under the regulation of diverse modifiers, myoblasts fuse with other neighboring myoblasts to generate multinucleated myotubes (10). During differentiation, the cell cycle is withdrawn and muscle-specific transcription factors activated. Mesodermal precursor cells with muscular lineages are differentiated into skeletal muscle or smooth muscle via the interplay of muscle-specific factors, including MyoD, myogenin, myogenic factor 5 (Myf5), muscle regulatory factor 4 (MRF4), and myocyte enhancer factor-2 (MEF2) (10).Histone modification enzymes have been implicated in muscle cell differentiation through the regulation of musclespecific gene expression (11,12). Chromatin modification enzymes such as histone acetyltransferases, deacetylases (HDACs), and chromatin remodeling factors have recently been reported to regulate MyoD activity during muscle differentiation. For example, the histone acetyltransferases p300 and p300/C...

The histone demethylase KDM4B interacts with MyoD to regulate myogenic differentiation in C2C12 myoblast cells

“…Similarly, enzymes that determine levels of methylation of histones have also been shown to regulate myogenic differentiation. SET7 and SETD3, which can methylate H3-K4 and often mark actively transcribed region, interact with MyoD to target muscle specific genes and thereby promote differentiation of myoblast cells [10,11]. In contrast, Suv39h1 that target H3-K9 and the polycomb protein Ezh2 that mediates methylation of H3-K27 inhibit myogenic differentiation by repressing muscle specific genes, while another H3-K9 specific histone methyltransferase (HMTase) G9a targets nonhistone substrates such as MEF2D and MyoD to inhibit the formation of differentiated myofibers [12][13][14][15].…”

The role of a newly identified SET domain-containing protein, SETD3, in oncogenesis

“…Thus, we conclude that the SETD3 protein is a fully active HMT for H3 with its activity dependent on the SET domain. Recently, independent studies also identified the zebrafish and mouse Setd3 genes via a bioinformatics approach 18,19 which also haematologica | 2013; 98(5) showed that SETD3 has HMT activity, in particular, on H3K4 and H3K36. 18 These studies used several H3 peptides instead of nucleosomes as substrates for the HMT assay.…”

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

“…Chem. (2016) 8(13) future science group Review Rogawski, Grembecka & Cierpicki SETD3 is a poorly characterized putative tumor suppressor that methylates H3K4 and H3K36 in vitro and in SETD3-transfected cells [117]. SETD3 expression is lower in renal cell tumors than normal renal tissues, and low expression of SETD3 is associated with shorter survival in renal cell carcinoma patients [118].…”