title: MyoD regulates p57kip2 expression by interacting with a distant cis-element and modifying a higher order chromatin structure.
abstract: The bHLH transcription factor MyoD, the prototypical master regulator of differentiation, directs a complex program of gene expression during skeletal myogenesis. The up-regulation of the cdk inhibitor p57kip2 plays a critical role in coordinating differentiation and growth arrest during muscle development, as well as in other tissues. p57kip2 displays a highly specific expression pattern and is subject to a complex epigenetic control driving the imprinting of the paternal allele. However, the regulatory mechanisms governing its expression during development are still poorly understood. We have identified an unexpected mechanism by which MyoD regulates p57kip2 transcription in differentiating muscle cells. We show that the induction of p57kip2 requires MyoD binding to a long-distance element located within the imprinting control region KvDMR1 and the consequent release of a chromatin loop involving p57kip2 promoter. We also show that differentiation-dependent regulation of p57kip2, while involving a region implicated in the imprinting process, is distinct and hierarchically subordinated to the imprinting control. These findings highlight a novel mechanism, involving the modification of higher order chromatin structures, by which MyoD regulates gene expression. Our results also suggest that chromatin folding mediated by KvDMR1 could account for the highly restricted expression of p57kip2 during development and, possibly, for its aberrant silencing in some pathologies.
authors: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università di Roma La Sapienza, Viale Regina Elena 324, Roma 00161, Italy.
authors: Anna
authors: A
authors: Busanello
authors: Cecilia
authors: C
authors: Battistelli
authors: Mariarosaria
authors: M
authors: Carbone
authors: Cassandra
authors: C
authors: Mostocotto
authors: Rossella
authors: R
authors: Maione
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis / Q000235:genetics*; D018392:Genomic Imprinting; D051657:KCNQ1 Potassium Channel / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D017570:MyoD Protein / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050436:Regulatory Elements, Transcriptional
chemical_list: D002843:Chromatin; D050761:Cyclin-Dependent Kinase Inhibitor p57; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D017570:MyoD Protein