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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Busanello A,Battistelli C,Carbone M,Mostocotto C,Maione R

doi

10.1093/nar/gks619

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

8266-75

issue

17

eissn

0305-1048

issn

1362-4962

pii

gks619

journal_volume

40

pub_type

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