Functional genomics and development of clinical genome editing strategies

功能基因组学和临床基因组编辑策略的开发

• 批准号: MC_UU_00029/4
• 负责人: James Davies
• 金额: $ 170.62万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00029%2F4
• 关键词: Functional; genomics; development; clinical; genome

The Davies laboratory aims to understand how the genome is read by the cells of the blood and bone marrow and how the sequence can be edited to treat human disease. This is important because genetic variation in bloodcells alters the susceptibility to many different human diseases including infection, autoimmune disease and malignancy. Genome editing of these cells has the potential to cure many diseases but this technology can only be safely used if we understand the effects of altering the genome sequence. Over 90% of all DNA sequences that are associated with human disease alter how genes are controlled rather than in the protein produced by the gene. The laboratory has world class expertise in developing new techniques for determining the physical structure of DNA within cells, which is key to understanding how the genome functions. We will use this technology to investigate the fundamental principles that control genes. We will also use it to map the key DNA sequences that control genes in important blood and bone marrow cell types. We aim to translate this by developing new and safer ways of editing the genome of bone marrow stem cells which can be transplanted to treat human disease.

戴维斯实验室的目标是了解血液和骨髓细胞是如何读取基因组的，以及如何编辑这些序列来治疗人类疾病。这一点很重要，因为血细胞的遗传变异改变了对许多不同人类疾病的易感性，包括感染、自身免疫性疾病和恶性肿瘤。对这些细胞进行基因组编辑有可能治愈许多疾病，但只有当我们了解改变基因组序列的影响时，这项技术才能安全使用。超过90%的与人类疾病相关的DNA序列改变了基因的控制方式，而不是基因产生的蛋白质。该实验室在开发确定细胞内DNA物理结构的新技术方面拥有世界一流的专业知识，这是了解基因组功能的关键。我们将利用这项技术来研究控制基因的基本原理。我们还将用它来绘制控制重要血液和骨髓细胞类型基因的关键DNA序列。我们的目标是通过开发新的、更安全的方法来编辑骨髓干细胞的基因组，从而将其移植到治疗人类疾病中。

项目成果

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.

Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF.

• DOI: 10.1038/s41467-022-29696-5
• 发表时间: 2022-04-19
• 期刊: Nature communications
• 影响因子: 16.6

GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells

• DOI: 10.1016/j.stem.2023.04.012
• 发表时间: 2023-05-04
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Turkalj, Sven;Jakobsen, Niels Asger;Vyas, Paresh
• 通讯作者: Vyas, Paresh

Pioneer activity distinguishes activating from non-activating SOX2 binding sites.

• DOI: 10.15252/embj.2022113150
• 发表时间: 2023-10-16
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: Maresca, Michela;van den Brand, Teun;Li, Hangpeng;Teunissen, Hans;Davies, James;de Wit, Elzo
• 通讯作者: de Wit, Elzo

Determining chromatin architecture with Micro Capture-C.

使用 Micro Capture-C 确定染色质结构。

• DOI: 10.1038/s41596-023-00817-8
• 发表时间: 2023
• 期刊: Nature protocols
• 影响因子: 14.8
• 作者: Hamley JC