The Epigenetic Control of Gene Expression in Leukaemia and Haematopoiesis

白血病和造血中基因表达的表观遗传控制

• 批准号: MC_UU_00016/6
• 负责人: Tom Milne
• 金额: $ 322.37万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00016%2F6
• 关键词: Epigenetic; Control; Gene; Expression; Leukaemia

There are many specialized cells in our body designed to carry out different specific tasks, and yet they all contain the same genetic information. During development, cells receive information that they translate into specific developmental outputs, usually without altering their DNA sequence. Changes in cell phenotype that do not alter the DNA sequence are referred to as “epigenetic”. Human diseases such as cancer often result from changes in gene expression patterns that are not always associated with DNA mutations, thus epigenetic changes are also a key mechanism in human disease. In living cells, genes do not exist as “naked” DNA, but as a highly conserved protein/DNA complex termed chromatin. The basic subunit of chromatin is the nucleosome, which consists of DNA wrapped around an octamer core of globular histone proteins, two each of H2A, H2B, H3, and H4.The N terminal "tails" of these histone proteins are chemically modified with "marks" such as methylation or acetylation. The specific carriers of epigenetic information have not been completely worked out, but emerging work over the past decade has suggested that epigenetic information is established in part by the modification of histone tails. We are specifically interested in how changes in histone methylation lead to transcriptional misregulation in human disease. As a system for asking specific questions about this very complex problem, I work on the Mixed Lineage Leukemia 1 (MLL1) protein, a histone methyltransferase that controls gene activation during development. Mutations in MLL1 also cause aggressive leukaemias in both children and adults. Specific information about MLL1 activity will not only provide potential therapeutic information for this subset of human leukemias, but will also have broader implications for stem cell development and the epigenetic regulation of gene expression in other human diseases.

我们体内有许多专门的细胞，旨在执行不同的特定任务，但它们都包含相同的遗传信息。在发育过程中，细胞接收到的信息被转化为特定的发育输出，通常不会改变它们的DNA序列。不改变DNA序列的细胞表型变化称为“表观遗传”。癌症等人类疾病通常是由基因表达模式的变化引起的，而这些变化并不总是与DNA突变有关，因此表观遗传变化也是人类疾病的关键机制。在活细胞中，基因不是以“裸露的”DNA形式存在，而是以高度保守的蛋白质/DNA复合体的形式存在，称为染色质。染色质的基本亚基是核小体，它由包裹在球状组蛋白八聚体核心上的DNA组成，组蛋白的H_2A、H_2B、H_3和H_4各有两个。这些组蛋白的N末端“尾巴”被甲基化或乙酰化等“标记”化学修饰。表观遗传信息的具体载体尚未完全弄清楚，但过去十年的新工作表明，表观遗传信息的建立部分是通过组蛋白尾巴的修饰来建立的。我们特别感兴趣的是组蛋白甲基化的变化如何导致人类疾病的转录调控失调。作为一个就这个非常复杂的问题提出具体问题的系统，我研究的是混合血统白血病1(MLL1)蛋白，这是一种组蛋白甲基转移酶，在发育过程中控制基因的激活。MLL1的突变也会导致儿童和成人的侵袭性白血病。关于MLL1活性的具体信息不仅将为这一人类白血病亚型提供潜在的治疗信息，而且还将对干细胞开发和其他人类疾病的基因表达的表观遗传调控具有更广泛的影响。

项目成果

BET inhibition disrupts transcription but retains enhancer-promoter contact.

• DOI: 10.1038/s41467-020-20400-z
• 发表时间: 2021-01-11
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Crump NT;Ballabio E;Godfrey L;Thorne R;Repapi E;Kerry J;Tapia M;Hua P;Lagerholm C;Filippakopoulos P;Davies JOJ;Milne TA
• 通讯作者: Milne TA

MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.

• DOI: 10.1038/s41467-023-40981-9
• 发表时间: 2023-08-25
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Crump, Nicholas T.;Smith, Alastair L.;Godfrey, Laura;Dopico-Fernandez, Ana M.;Denny, Nicholas;Harman, Joe R.;Hamley, Joseph C.;Jackson, Nicole E.;Chahrour, Catherine;Riva, Simone;Rice, Siobhan;Kim, Jaehoon;Basrur, Venkatesha;Fermin, Damian;Elenitoba-Johnson, Kojo;Roeder, Robert G.;Allis, C. David;Roberts, Irene;Roy, Anindita;Geng, Huimin;Davies, James O. J.;Milne, Thomas A.
• 通讯作者: Milne, Thomas A.

BET inhibition disrupts transcription but retains enhancer-promoter contact

BET 抑制会破坏转录但保留增强子-启动子接触

• DOI: 10.1101/848325
• 发表时间: 2019
• 作者: Crump N

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

• DOI: 10.1016/j.ccell.2018.01.006
• 发表时间: 2018-02-12
• 期刊: CANCER CELL
• 影响因子: 50.3
• 作者: Booth, Christopher A. G.;Barkas, Nikolaos;Mead, Adam J.
• 通讯作者: Mead, Adam J.

Author Correction: Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture.

作者更正：Capture-C：一种用于高分辨率染色体构象捕获的模块化且灵活的方法。

• DOI: 10.1038/s41596-023-00860-5
• 发表时间: 2023
• 期刊: Nature protocols
• 影响因子: 14.8
• 作者: Downes DJ