Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, California.
Gastroenterology. 2021 Jun;160(7):2267-2282. doi: 10.1053/j.gastro.2021.03.036. Epub 2021 Mar 26.
Genetic mutations or regulatory failures underlie cellular malfunction in many diseases, including colorectal cancer and inflammatory bowel diseases. However, mutational defects alone fail to explain the complexity of such disorders. Epigenetic regulation-control of gene action through chemical and structural changes of chromatin-provides a platform to integrate multiple extracellular inputs and prepares the cellular genome for appropriate gene expression responses. Coregulation by polycomb repressive complex 2-mediated trimethylation of lysine 27 on histone 3 and DNA methylation has emerged as one of the most influential epigenetic controls in colorectal cancer and many other diseases, but molecular details remain inadequate. Here we review the molecular interplay of these epigenetic features in relation to gastrointestinal development, homeostasis, and disease biology. We discuss other epigenetic mechanisms pertinent to the balance of trimethylation of lysine 27 on histone 3 and DNA methylation and their actions in gastrointestinal cancers. We also review the current molecular understanding of chromatin control in the pathogenesis of inflammatory bowel diseases.
遗传突变或调控失灵是许多疾病（包括结直肠癌和炎症性肠病）中细胞功能障碍的基础。然而，突变缺陷本身并不能解释这些疾病的复杂性。表观遗传调控——通过染色质的化学和结构变化来控制基因的作用——为整合多种细胞外输入并为适当的基因表达反应准备细胞基因组提供了一个平台。多梳抑制复合物 2 介导的组蛋白 3 赖氨酸 27 三甲基化和 DNA 甲基化的共调控已成为结直肠癌和许多其他疾病中最具影响力的表观遗传调控之一，但分子细节仍不充分。在这里，我们回顾了这些表观遗传特征与胃肠道发育、稳态和疾病生物学相关的分子相互作用。我们讨论了与组蛋白 3 赖氨酸 27 三甲基化和 DNA 甲基化平衡相关的其他表观遗传机制及其在胃肠道癌症中的作用。我们还回顾了目前对炎症性肠病发病机制中染色质控制的分子理解。
