Integration of the Transcription Factor-Regulated and Epigenetic Mechanisms in the Control of Keratinocyte Differentiation.
Integration of the Transcription Factor-Regulated and Epigenetic Mechanisms in the Control of Keratinocyte Differentiation.
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转录因子调节和表观遗传机制在控制角质形成细胞分化中的整合。
DOI：
10.1038/jidsymp.2015.37
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发表时间：
2015-11
影响因子：
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通讯作者：
Botchkarev, Vladimir A
中科院分区：
文献类型：
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作者：
Botchkarev, Vladimir A
表皮分化程序在几个水平上受到调节，包括信号传导途径、谱系特异性转录因子和表观遗传调节因子，这些调节因子建立了协调良好的终末分化过程，导致表皮屏障的形成。表观遗传调控机制在几个水平上运作，包括调节共价DNA/组蛋白修饰，以及通过高阶染色质重塑在基因及其增强子元件之间建立长程拓扑相互作用。表观遗传调节因子对角质形成细胞（KC）的染色质具有激活和抑制作用：其中一些促进终末分化，另一些刺激祖细胞增殖，以及抑制终末分化相关基因的过早激活。转录因子调节和表观遗传机制高度相关，p63转录因子通过直接控制基因组组织者Satb 1和ATP依赖性染色质重塑因子Brg 1在KC特异性基因位点的高阶染色质重塑中发挥重要作用。然而，还需要额外的努力来充分了解不同转录因子和表观遗传调节因子在控制KC分化中相互作用的复杂性。进一步了解这些相互作用及其在不同病理性皮肤病中的变化，将有助于通过靶向表观遗传调节剂和调节KC中的染色质组织来开发治疗皮肤病的新方法。
The epidermal differentiation program is regulated at several levels including signaling pathways, lineage-specific transcription factors, and epigenetic regulators that establish well-coordinated process of terminal differentiation resulting in formation of the epidermal barrier. The epigenetic regulatory machinery operates at several levels including modulation of covalent DNA/histone modifications, as well as through higher-order chromatin remodeling to establish long-range topological interactions between the genes and their enhancer elements. Epigenetic regulators exhibit both activating and repressive effects on chromatin in keratinocytes (KCs): whereas some of them promote terminal differentiation, the others stimulate proliferation of progenitor cells, as well as inhibit premature activation of terminal differentiation-associated genes. Transcription factor-regulated and epigenetic mechanisms are highly connected, and the p63 transcription factor has an important role in the higher-order chromatin remodeling of the KC-specific gene loci via direct control of the genome organizer Satb1 and ATP-dependent chromatin remodeler Brg1. However, additional efforts are required to fully understand the complexity of interactions between distinct transcription factors and epigenetic regulators in the control of KC differentiation. Further understanding of these interactions and their alterations in different pathological skin conditions will help to progress toward the development of novel approaches for the treatment of skin disorders by targeting epigenetic regulators and modulating chromatin organization in KCs.