A New Isoform of the Histone Demethylase JMJD2A/KDM4A Is Required for Skeletal Muscle Differentiation

Autor: Laure Verrier, Didier Trouche, Fabrice Escaffit, Catherine Chailleux, Marie Vandromme
Přispěvatelé: Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2011
Předmět:
Cancer Research
Cellular differentiation
MESH: Protein Isoforms
Epigenesis
Genetic
Myoblasts
Mice
0302 clinical medicine
Transcriptional regulation
Protein Isoforms
MESH: Animals
MESH: Epigenesis
Genetic
Cells
Cultured
Genetics (clinical)
Histone Demethylases
Regulation of gene expression
MESH: Muscle
Skeletal
0303 health sciences
biology
Myogenesis
Cell Differentiation
Genetics and Genomics/Gene Expression
Chromatin
030220 oncology & carcinogenesis
C2C12
MESH: Cells
Cultured
Research Article
MESH: Cell Differentiation
lcsh:QH426-470
Cell Biology/Developmental Molecular Mechanisms
Transfection
MESH: Chromatin
03 medical and health sciences
MESH: Histone Demethylases
Genetics
Animals
Humans
MESH: Myoblasts
Epigenetics
Molecular Biology/Chromatin Structure
Muscle
Skeletal
MESH: Mice
Molecular Biology
Cell Biology/Gene Expression
Ecology
Evolution
Behavior and Systematics
Myogenin
030304 developmental biology
MESH: Humans
MESH: Transfection
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
Molecular Biology/Transcription Initiation and Activation
Molecular biology
lcsh:Genetics
NIH 3T3 Cells
biology.protein
Demethylase
MESH: NIH 3T3 Cells
Zdroj: PLoS Genetics
PLoS Genetics, Public Library of Science, 2011, 7 (6), pp.e1001390. ⟨10.1371/journal.pgen.1001390⟩
PLoS Genetics, Vol 7, Iss 6, p e1001390 (2011)
ISSN: 1553-7404
1553-7390
DOI: 10.1371/journal.pgen.1001390
Popis: 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 (ΔN-JMJD2A). The amount of ΔN-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, ΔN-JMJD2A is necessary for myotube formation and muscle-specific gene expression. Moreover, ΔN-JMJD2A promotes MyoD-induced conversion of NIH3T3 cells into muscle cells. ChIP-on-chip analysis indicates that ΔN-JMJD2A binds to genes mainly involved in transcriptional control and that this binding is linked to gene activation. ΔN-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 ΔN-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.
Author Summary Gene expression is regulated in part by so-called “epigenetic” mechanisms—modifications of the DNA itself or of proteins associated with DNA (such as histones). We have studied an enzyme that affects these histone modifications—the histone demethylase JMJD2A—and its role in muscle differentiation. Muscle differentiation is tightly controlled during the development of the organism to ensure that muscle forms at the right place and at the right time. Muscle precursor cells are prevented from differentiating by silencing of a “master gene” of muscle differentiation called Myog. This silencing is brought about by specific epigenetic modifications of the Myog gene that are removed when the precursor cell receives a signal to differentiate. Here, we have discovered a new isoform of JMJD2A that is upregulated during muscle differentiation and that is required for activation of Myog. Binding of this JMJD2A isoform to the Myog gene is probably a crucial step in inducing muscle differentiation. Our findings thus uncover the existence of a second isoform of the histone demethylase JMJD2A important for muscle differentiation and suggest that the balance between JMJD2A isoforms is important for controlling the fate of muscle precursor cells.
Databáze: OpenAIRE
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