a Department of Cellular and Molecular Medicine, Faculty of Medicine , University of Ottawa , Ottawa , Ontario , Canada.
b Department of Pathology and Laboratory Medicine, Faculty of Medicine , University of Ottawa , Ottawa , Ontario , Canada.
Epigenetics. 2018;13(6):642-654. doi: 10.1080/15592294.2018.1489659. Epub 2018 Jul 30.
Molecular regulation of stem cell differentiation is exerted through both genetic and epigenetic determinants over distal regulatory or enhancer regions. Understanding the mechanistic action of active or poised enhancers is therefore imperative for control of stem cell differentiation. Based on the genome-wide co-occurrence of different epigenetic marks in committed proliferating myoblasts, we have previously generated a 14-state chromatin state model to profile rexinoid-responsive histone acetylation in early myoblast differentiation. Here, we delineate the functional mode of transcription regulators during early myogenic differentiation using genome-wide chromatin state association. We define a role of transcriptional coactivator p300, when recruited by muscle master regulator MyoD, in the establishment and regulation of myogenic loci at the onset of myoblast differentiation. In addition, we reveal an enrichment of loci-specific histone acetylation at p300 associated active or poised enhancers, particularly when enlisted by MyoD. We provide novel molecular insights into the regulation of myogenic enhancers by p300 in concert with MyoD. Our studies present a valuable aptitude for driving condition-specific chromatin state or enhancers pharmacologically to treat muscle-related diseases and for the identification of additional myogenic targets and molecular interactions for therapeutic development.
MRF: Muscle regulatory factor; HAT: Histone acetyltransferase; CBP: CREB-binding protein; ES: Embryonic stem; ATCC: American type culture collection; DM: Differentiation medium; DMEM: Dulbecco's Modified Eagle Medium; GM: Growth medium; GO: Gene ontology; GREAT: Genomic regions enrichment of annotations tool; FPKM: Fragments per kilobase of transcript per million; GEO: Gene expression omnibus; MACS: Model-based analysis for ChIP-seq.
通过对远端调控或增强子区域的遗传和表观遗传决定因素，对干细胞分化的分子调控进行发挥。因此，了解活性或静止增强子的机械作用对于控制干细胞分化是至关重要的。基于在分化中的定向增殖的成肌细胞中不同表观遗传标记的全基因组共发生，我们之前已经生成了一个 14 状态染色质状态模型，以描绘早期成肌细胞分化中视黄酸反应性组蛋白乙酰化。在这里，我们使用全基因组染色质状态关联来描绘早期成肌分化过程中转录调节因子的功能模式。我们定义了转录共激活因子 p300 的作用，当它被肌肉主调节因子 MyoD 招募时，在成肌细胞分化起始时建立和调节成肌基因座。此外，我们揭示了在 p300 相关的活性或静止增强子处的局部特异性组蛋白乙酰化的富集，特别是当被 MyoD 募集时。我们提供了关于 p300 与 MyoD 协同调节成肌增强子的新分子见解。我们的研究为通过药理学驱动条件特异性染色质状态或增强子提供了有价值的能力，以治疗与肌肉相关的疾病，并鉴定其他成肌靶标和分子相互作用，以进行治疗开发。
MRF：肌肉调节因子；HAT：组蛋白乙酰转移酶；CBP：CREB 结合蛋白；ES：胚胎干细胞；ATCC：美国典型培养物保藏中心；DM：分化培养基；DMEM：杜尔贝科改良鹰培养基；GM：生长培养基；GO：基因本体论；GREAT：注释工具的基因组区域富集；FPKM：每百万转录片段每千碱基的片段数；GEO：基因表达综合数据库；MACS：用于 ChIP-seq 的基于模型的分析。
