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Circadian Regulation of Myod1 Transcription

Myod1 转录的昼夜节律调节

基本信息

批准号：
7624575
负责人：
JOHN Joseph MCCARTHY
金额：
$ 7.18万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2010-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The myogenic differentiation 1 (Myodl) gene encodes a basic helix-loop-helix transcription factor that is a master regulator of skeletal muscle lineage determination during embryonic development. The post-natal function of Myodl is not well understood but a deficit in the specific tension of Myodl (-/-) mice, in addition to their impaired regenerative ability, intimate a significant role in adult skeletal muscle. We recently identified the Myodl transcript in adult skeletal muscle as having a robust circadian pattern of expression and this pattern of expression was absent in muscle of homozygous Clock mutant mice, suggesting Myodl is a clockcontrolled gene. The long-range goal of the project is to understand the circadian function of Myodl in adult skeletal muscle. As a first step toward this goal, the objective of this proposal will be to determine if the coreclock transcription factors Clock and Email are directly involved in the regulation of Myodl transcription. The primary hypothesis of this application is that Myodl is a direct transcriptional target of the CLOCK:BMAL1 heterodimer. The hypothesis will be tested by pursuing the following three specific aims: 1) use the Myodl DRRIoxP and CEIoxP mice to determine the role of the distal regulatory region (DRR) and the core enhancer (CE) of the Myodl promoter in the circadian regulation of Myodl transcription, 2) determine the ability of core-clock transcription factors CLOCK and BMAL1 to transactivate Myodl reporter genes and 3) determine if CLOCK and BMAL1 are bound to the endogenous Myodl promoter by chromatin immunoprecipitation (ChIP) assay. The discovery of Myodl as a circadianly expressed gene is an exciting discovery because it provides a completely novel paradigm for thinking about the post-natal function of Myodl and establishes a potential link between master regulators of circadian rhythms and tissue-specific expression. A better understanding of how Myodl transcription is regulated in the adult is expected to provide a foundation for understanding the mechanisms underlying the altered expression of Myodl in such diseases as muscular dystrophy and sarcopenia.

描述（由申请人提供）：肌源性分化1（Myodl）基因编码碱性螺旋-环-螺旋转录因子，其是胚胎发育期间骨骼肌谱系决定的主要调节因子。Myodl的出生后功能尚未得到很好的理解，但是Myodl（-/-）小鼠的特定张力的缺陷，除了它们受损的再生能力之外，暗示了在成年骨骼肌中的重要作用。我们最近鉴定了成年骨骼肌中的Myodl转录物具有稳健的昼夜节律表达模式，并且这种表达模式在纯合Clock突变小鼠的肌肉中不存在，表明Myodl是时钟控制的基因。该项目的长期目标是了解Myodl在成人骨骼肌中的昼夜节律功能。作为实现这一目标的第一步，本提案的目的将是确定核心锁转录因子Clock和Email是否直接参与Myodl转录的调节。本申请的主要假设是Myodl是CLOCK：BMALl异二聚体的直接转录靶标。将通过追求以下三个具体目标来检验这一假设：1）使用Myodl DRRIoxP和CEIoxP小鼠来确定Myodl启动子的远端调节区（DRR）和核心增强子（CE）在Myodl转录的昼夜节律调节中的作用，2）确定核心时钟转录因子CLOCK和BMAL 1反式激活Myodl报告基因的能力，和通过染色质免疫沉淀（ChIP）测定确定CLOCK和BMAL 1是否与内源性Myodl启动子结合。Myodl作为昼夜节律表达基因的发现是一个令人兴奋的发现，因为它为思考Myodl的出生后功能提供了一个全新的范式，并在昼夜节律的主要调节因子和组织特异性表达之间建立了潜在的联系。更好地理解Myodl转录在成人中是如何调节的，预期将为理解Myodl在诸如肌营养不良症和肌肉减少症等疾病中的表达改变的机制提供基础。