Sanford-Burnham Medical Research Institute, Sanford Children's Health Research Center, La Jolla, CA, USA.
FEBS J. 2013 Sep;280(17):4014-25. doi: 10.1111/febs.12383. Epub 2013 Jul 15.
During embryonic development, pluripotent cells are genetically committed to specific lineages by the expression of cell-type-specific transcriptional activators that direct the formation of specialized tissues and organs in response to developmental cues. Chromatin-modifying proteins are emerging as essential components of the epigenetic machinery, which establishes the nuclear landscape that ultimately determines the final identity and functional specialization of adult cells. Recent evidence has revealed that discrete populations of adult cells can retain the ability to adopt alternative cell fates in response to environmental cues. These cells include conventional adult stem cells and a still poorly defined collection of cell types endowed with facultative phenotype and functional plasticity. Under physiological conditions or adaptive states, these cells cooperate to support tissue and organ homeostasis, and to promote growth or compensatory regeneration. However, during chronic diseases and aging these cells can adopt a pathological phenotype and mediate maladaptive responses, such as the formation of fibrotic scars and fat deposition that progressively replaces structural and functional units of tissues and organs. The molecular determinants of these phenotypic transitions are only emerging from recent studies that reveal how dynamic chromatin states can generate flexible epigenetic landscapes, which confer on cells the ability to retain partial pluripotency and adapt to environmental changes. This review summarizes our current knowledge on the role of the epigenetic machinery as a 'filter' between genetic commitment and environmental signals in cell types that can alternatively promote skeletal muscle regeneration or fibro-adipogenic degeneration.
在胚胎发育过程中，多能细胞通过表达细胞类型特异性转录激活因子，对发育信号作出反应，从而被遗传地分配到特定的谱系中，这些转录激活因子指导专门组织和器官的形成。染色质修饰蛋白正成为表观遗传机制的重要组成部分，表观遗传机制建立了核景观，最终决定成年细胞的最终身份和功能特化。最近的证据表明，离散的成年细胞群体可以保留在环境信号作用下采用替代细胞命运的能力。这些细胞包括传统的成年干细胞和一组功能仍不明确的细胞类型，它们具有兼性表型和功能可塑性。在生理条件或适应状态下，这些细胞共同支持组织和器官的稳态，并促进生长或代偿性再生。然而，在慢性疾病和衰老过程中，这些细胞可能会表现出病理表型，并介导适应性反应，例如纤维化疤痕的形成和脂肪沉积，这些反应逐渐取代组织和器官的结构和功能单位。这些表型转变的分子决定因素仅从最近的研究中显现出来，这些研究揭示了动态染色质状态如何产生灵活的表观遗传景观，使细胞能够保持部分多能性并适应环境变化。这篇综述总结了我们目前对表观遗传机制在可替代地促进骨骼肌再生或纤维脂肪变性的细胞类型中作为“过滤器”的作用的认识，该机制在遗传决定和环境信号之间发挥作用。
