a new isoform of the histone demethylase jmjd2akdm4a is required for skeletal muscle differentiation一个新的同种型的组蛋白demethylase jmjd2akdm4a需要骨骼肌分化.pdfVIP

A New Isoform of the Histone Demethylase JMJD2A/ KDM4A Is Required for Skeletal Muscle Differentiation Laure Verrier1,2, Fabrice Escaffit1,2, Catherine Chailleux1,2, Didier Trouche1,2., Marie Vandromme1,2.* ´ 1 Universite de Toulouse, UPS, LBCMCP, F-31062, Toulouse, France, 2 CNRS, LBCMCP, F-31062, Toulouse, France Abstract In proliferating myoblasts, muscle specific genes are silenced by epigenetic modifications at their promoters, including histone H3K9 methylation. Derepression of the promoter of the gene encoding the myogenic factor myogenin (Myog) is key for initiation of muscle differentiation. The mechanism of H3K9 demethylation at the Myog promoter is unclear, however. Here, we identify an isoform of the histone demethylase JMJD2A/KDM4A that lacks the N-terminal demethylase domain (DN-JMJD2A). The amount of DN-JMJD2A increases during differentiation of C2C12 myoblasts into myotubes. Genome-wide expression profiling and exon-specific siRNA knockdown indicate that, in contrast to the full-length protein, DN-JMJD2A is necessary for myotube formation and muscle-specific gene expression. Moreover, DN-JMJD2A promotes MyoD-induced conversion of NIH3T3 cells into muscle cells. ChIP-on-chip analysis indicates that DN-JMJD2A binds to genes mainly involved in transcriptional control and that this binding is linked to gene activation. DN-JMJD2A is recruited to the Myog promoter at the onset of differentiation. This binding is essential to promote the demethylation of H3K9me2 and H3K9me3. We conclude that induction of the DN-JMJD2A isoform is crucial for muscle differentiation: by directing the removal of repressive chromatin marks at the Myog promoter, it promotes transcriptional activation of the Myog gene and thus contributes to initiation of muscle-specific gene expression.