Andrew J Fritz, Prachi N Ghule, Rabail Toor, Louis Dillac, Jonah Perelman, Joseph Boyd, Jane B Lian, Johnathan A R Gordon, Seth Frietze, Andre Van Wijnen, Janet L Stein, Gary S Stein
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引用次数: 0
摘要
高阶基因组组织支持组蛋白基因的激活,以响应细胞周期调控线索,从而在G1/S期转换时以表观遗传学方式介导对转录的严格控制。组蛋白基因座体(HLBs)是动态、非膜状、相分离的核域,组蛋白基因表达的调控机制在此组织和组装,以支持对组蛋白基因的时空表观遗传学控制。HLB 是支持 DNA 复制依赖性组蛋白 mRNA 合成和处理的分子枢纽。这些调控微环境支持单个拓扑关联域(TAD)内非毗连组蛋白基因之间的长程基因组相互作用。HLB 在 G1/S 过渡期对细胞周期蛋白 E/CDK2/NPAT/HINFP 通路的激活做出反应。HINFP 及其辅助激活因子 NPAT 在 HLB 中形成一个复合物,控制组蛋白 mRNA 的转录,以支持组蛋白的合成和新复制 DNA 的包装。HINFP 的缺失会影响 H4 基因的表达和染色质的形成,从而可能导致 DNA 损伤并阻碍细胞周期的进展。HLB 为亚核域的高阶基因组组织提供了一个范例,该亚核域在 Cyclin E/CDK2 信号的作用下执行着细胞周期控制的强制性功能。了解局部定义的核域中协调和时空组织的调控程序,有助于深入了解细胞信号通路的分子基础结构,这些通路介导了对生长和分化表型的生物控制,并在癌症中受到损害。
Spatiotemporal Epigenetic Control of the Histone Gene Chromatin Landscape during the Cell Cycle.
Higher-order genomic organization supports the activation of histone genes in response to cell cycle regulatory cues that epigenetically mediates stringent control of transcription at the G1/S-phase transition. Histone locus bodies (HLBs) are dynamic, non-membranous, phase-separated nuclear domains where the regulatory machinery for histone gene expression is organized and assembled to support spatiotemporal epigenetic control of histone genes. HLBs provide molecular hubs that support synthesis and processing of DNA replication-dependent histone mRNAs. These regulatory microenvironments support long-range genomic interactions among non-contiguous histone genes within a single topologically associating domain (TAD). HLBs respond to activation of the cyclin E/CDK2/NPAT/HINFP pathway at the G1/S transition. HINFP and its coactivator NPAT form a complex within HLBs that controls histone mRNA transcription to support histone protein synthesis and packaging of newly replicated DNA. Loss of HINFP compromises H4 gene expression and chromatin formation, which may result in DNA damage and impede cell cycle progression. HLBs provide a paradigm for higher-order genomic organization of a subnuclear domain that executes an obligatory cell cycle-controlled function in response to cyclin E/CDK2 signaling. Understanding the coordinately and spatiotemporally organized regulatory programs in focally defined nuclear domains provides insight into molecular infrastructure for responsiveness to cell signaling pathways that mediate biological control of growth, differentiation phenotype, and are compromised in cancer.
期刊介绍:
Critical ReviewsTM in Eukaryotic Gene Expression presents timely concepts and experimental approaches that are contributing to rapid advances in our mechanistic understanding of gene regulation, organization, and structure within the contexts of biological control and the diagnosis/treatment of disease. The journal provides in-depth critical reviews, on well-defined topics of immediate interest, written by recognized specialists in the field. Extensive literature citations provide a comprehensive information resource.
Reviews are developed from an historical perspective and suggest directions that can be anticipated. Strengths as well as limitations of methodologies and experimental strategies are considered.