Mechanism of Epigenetic Inheritance

表观遗传机制

• 批准号: 10796601
• 负责人: Zhiguo Zhang
• 金额: $ 5.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796601
• 关键词: Binding Proteins; Bioinformatics; Cell Cycle; Cells; Chromatin; Complex; Coupled; Cryoelectron Microscopy; DNA; DNA biosynthesis; DNA replication fork; Elements; Endogenous Retroviruses; Epigenetic Process; Euchromatin; Eukaryotic Cell; Genomic DNA; Heterochromatin; Histones; Human Resources; Immunotherapy; Inherited; Laboratories; Methods; Modification; Molecular; Mus; Nucleosomes; Peptide Sequence Determination; Process; Proteins; Repression; S phase; Yeasts; cancer cell; cost; daughter cell; embryonic stem cell; genome integrity; histone modification; insight; novel; response; transmission process

Abstract In eukaryotic cells, genomic DNA is packaged into chromatin that encodes epigenetic information and maintain genome integrity. Chromatin is further organized into distinct functional domains, such as heterochromatin and euchromatin, that contain different post-translational histone modifications (PTM). How different chromatin states are inherited during S phase of the cell cycle is one of the most challenging questions in the chromatin and epigenetic fields. The “first” step in this complex process is the assembly of replicated DNA into nucleosomes using both parental and newly-synthesized histones in a process that is tightly coupled to ongoing DNA synthesis. We have been studying how nucleosomes are formed following DNA replication and have made multiple major contributions to this process. However, how parental histone (H3-H4)2 tetramers, the primary carrier of epigenetic modifications, are transferred to replicating DNA is still poorly understood, which hinders our understanding of the transmission of epigenetic information into daughter cells. The major challenge to understanding parental histone (H3-H4)2 assembly is a lack of methods to track this process. We have developed the eSPAN (enrichment and Sequencing Protein- Associated Nascent DNA) method that can discern whether a protein binds to leading or lagging strands of DNA replication forks in both yeast and mouse embryonic stem (ES) cells. This method makes it possible to identify factors that function in nucleosome assembly of parental histone (H3-H4)2. Moreover, we discovered that cells defective in parental histone transfer compromise the repression of endogenous retrovirus (ERVs), repetitive DNA elements that are normally silenced via a heterochromatin-based mechanism. Others show that ERV reactivation in cancer cells leads to increased response to immunotherapy. In this proposal, we will elucidate the molecular mechanisms whereby parental (H3-H4)2 are reassembled into nucleosomes following DNA replication in yeast and mouse ES cells and determine how deficiencies in this process impact ERV silencing. Together, these studies will address fundamental questions regarding chromatin replication and epigenetic inheritance, while also providing novel insights into a major epigenetic mechanism that boosts the response of cancer cells to immunotherapy.

抽象的 在真核细胞中，基因组 DNA 被包装到染色质中，染色质编码表观遗传信息并维持 基因组完整性。染色质进一步组织成不同的功能域，例如异染色质和 常染色质，包含不同的翻译后组蛋白修饰 (PTM)。染色质有何不同 细胞周期 S 期状态的遗传是细胞周期中最具挑战性的问题之一 染色质和表观遗传领域。这个复杂过程的“第一步”是将复制的 DNA 组装成 核小体在与正在进行的紧密耦合的过程中同时使用亲本和新合成的组蛋白 DNA合成。我们一直在研究 DNA 复制后核小体是如何形成的，并已 对此过程做出了多项重大贡献。然而，亲本组蛋白 (H3-H4)2 四聚体如何 表观遗传修饰的主要载体如何转移到复制 DNA 中仍然知之甚少，这 阻碍了我们对表观遗传信息向子细胞传递的理解。主要 理解亲本组蛋白 (H3-H4)2 组装的挑战是缺乏追踪此过程的方法 过程。我们开发了 eSPAN（蛋白质相关新生 DNA 富集和测序） 可以辨别蛋白质是否与 DNA 复制叉的前导链或滞后链结合的方法 酵母和小鼠胚胎干 (ES) 细胞。该方法可以识别在其中发挥作用的因素 亲代组蛋白 (H3-H4)2 的核小体组装。此外，我们发现亲代细胞有缺陷 组蛋白转移会损害内源性逆转录病毒 (ERV) 的抑制，这是一种重复的 DNA 元件， 通常通过基于异染色质的机制来沉默。其他研究表明，ERV 在癌症中重新激活 细胞导致对免疫疗法的反应增强。在本提案中，我们将阐明分子 酵母中 DNA 复制后亲本 (H3-H4)2 重新组装成核小体的机制 和小鼠 ES 细胞，并确定该过程中的缺陷如何影响 ERV 沉默。在一起，这些 研究将解决有关染色质复制和表观遗传的基本问题，同时 还提供了对增强癌细胞反应的主要表观遗传机制的新见解 免疫疗法。

项目成果

A mechanism for preventing asymmetric histone segregation onto replicating DNA strands.

• DOI: 10.1126/science.aat8849
• 发表时间: 2018-09-28
• 期刊: Science (New York, N.Y.)
• 作者: Yu C;Gan H;Serra-Cardona A;Zhang L;Gan S;Sharma S;Johansson E;Chabes A;Xu RM;Zhang Z
• 通讯作者: Zhang Z

CHAF1B Overexpression: A Brake for the Differentiation of Leukemia Cells.

• DOI: 10.1016/j.ccell.2018.10.011
• 发表时间: 2018-11-12
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Li Q;Zhang X;Zhang Z
• 通讯作者: Zhang Z

RPA Interacts with HIRA and Regulates H3.3 Deposition at Gene Regulatory Elements in Mammalian Cells.

• DOI: 10.1016/j.molcel.2016.11.030
• 发表时间: 2017-01-19
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Zhang H;Gan H;Wang Z;Lee JH;Zhou H;Ordog T;Wold MS;Ljungman M;Zhang Z
• 通讯作者: Zhang Z

Multisite Substrate Recognition in Asf1-Dependent Acetylation of Histone H3 K56 by Rtt109.

Rtt109 对 Asf1 依赖性组蛋白 H3 K56 乙酰化的多位点底物识别

• DOI: 10.1016/j.cell.2018.07.005
• 发表时间: 2018-08-09
• 期刊: Cell
• 影响因子: 64.5
• 作者: Zhang L;Serra-Cardona A;Zhou H;Wang M;Yang N;Zhang Z;Xu RM
• 通讯作者: Xu RM

Coordination of histone chaperones for parental histone segregation and epigenetic inheritance.

亲代组蛋白分离和表观遗传的组蛋白伴侣的协调。

• DOI: 10.1101/gad.351278.123
• 发表时间: 2024
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Fang,Yimeng;Hua,Xu;Shan,Chun-Min;Toda,Takenori;Qiao,Feng;Zhang,Zhiguo;Jia,Songtao
• 通讯作者: Jia,Songtao