Critical role of TCF-1 on the epigenetic identity of memory T cells

TCF-1 对记忆 T 细胞表观遗传特性的关键作用

基本信息

批准号：
10549303
负责人：
Golnaz Vahedi
金额：
$ 45.17万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549303
关键词：
3-Dimensional Adaptive Immune System Area Binding Binding Sites Biological Assay CD8-Positive T-Lymphocytes Cell physiology Cells Chromatin Collaborations Combined Modality Therapy Consensus Data Development Disease Effector Cell Epigenetic Process Event FOXO1A gene Flow Cytometry Foundations Gene Expression Profile Generations Genes Genome Genomic Segment Goals In Vitro Infection Machine Learning Maps Mediating Memory Molecular Monitor Organ Transplantation Outcome Peripheral Proteins Regulatory Element Research Resolution Role Site T cell differentiation T cell response T memory cell T-Cell Activation T-Cell Development T-Lymphocyte TCF Transcription Factor Techniques Tertiary Protein Structure Testing Thymus Gland Translating cell type chronic infection epigenome epigenomics immunoregulation in vivo member mutant novel novel therapeutic intervention pathogen permissiveness synergism tool transcription factor transcriptomics

项目摘要

The goal of this proposal is to study the role of transcription factor TCF-1 in determining the epigenetic identity of memory CD8+ T cells. Our adaptive immune system has evolved a unique capacity to remember a pathogen through the generation of memory T cells, which protect the host in the event of reinfection. A better understanding of memory T cell differentiation is crucial for developing strategies to limit T cell responses in organ transplantation or enhance T cell responses during chronic infections. Although it is known that the transcription factor TCF-1 is required for memory CD8+ T cell function, the mechanisms through which this protein controls memory T cell fate remain unclear. Recently, we discovered that a mechanism through which TCF-1 controls the development of T cells relates to its unprecedented ability to create the chromatin accessibility landscape of naïve T cells. We found that TCF-1 is selectively enriched at genomic regions that become accessible at the earliest stages of development and is required for the accessibility of these regulatory elements. At the single-cell level, TCF-1 can dictate a coordinate opening of chromatin in T cells. Moreover, ectopic TCF-1 can directly erase repressive chromatin marks in non-T cells, generating de novo open chromatin and inducing the expression of T cell genes. While our recent data determined the novel role of TCF-1 on the epigenome during T cell development, our findings also raised another critical question: what is the role of TCF-1 on the epigenetic identity of memory T cells? We hypothesize that TCF-1 in cooperation with transcription factor partners defines the epigenetic landscape of memory T cells. Our new preliminary data further indicate that TCF-1 expression post T cell activation in vitro can lead to gains in chromatin accessibility at pro-memory genes. However, it remains unclear if TCF-1 expression in T cells responding to an infection can create the epigenetic identity of memory T cells. The domains of TCF-1 required for targeting the chromatin and its potential cooperating factors also remain unknown. How TCF-1 dependent changes on the epigenome relate to pro-memory genes needs to be defined. To answer these questions, we will interrogate the effect of TCF-1 and its potential partners on the chromatin state and accessibility of CD8+ T cells in vitro. Using the state-of-the-art tools, we will generate the map of TCF-1 dependent 3D genome organization and define how changes on the epigenome relate to memory genes. We will further translate these findings in vivo exploiting single-cell epigenomic, transcriptomic, and flow cytometry assays. The expected outcome of this proposal is a detailed understanding of the fundamental interaction between TCF-1 and the chromatin in peripheral T cells which can be exploited to devise combination therapies including epigenetic editing to selectively alter T cell fate at will.

该建议的目的是研究转录因子TCF-1在确定表观遗传身份中的作用记忆CD8+ T细胞的记忆。我们的自适应免疫系统已经发展出独特的能力来记住病原体通过生成记忆T细胞，在重新感染时保护宿主。更好了解记忆T细胞分化对于制定限制T细胞反应的策略至关重要器官移植或增强慢性感染期间T细胞反应。虽然知道记忆CD8+ T细胞功能所必需的转录因子TCF-1是该机制蛋白质控制记忆T细胞命运尚不清楚。最近，我们发现了一种机制 TCF-1控制T细胞的发展与其前所未有的创建染色质的能力有关幼稚T细胞的可及性景观。我们发现TCF-1在基因组区域有选择地富集在开发的最早阶段可以访问，这是这些可访问性所必需的监管要素。在单细胞水平上，TCF-1可以决定T细胞中染色质的坐标开口。此外，异位TCF-1可以直接消除非T细胞中的反射性染色质标记，从而产生从头开始开放染色质并诱导T细胞基因的表达。尽管我们最近的数据决定了新角色在T细胞开发过程中TCF-1上的TCF-1，我们的发现也提出了另一个关键问题：什么 TCF-1在记忆T细胞的表观遗传身份中的作用是吗？我们假设合作中的TCF-1 使用转录因子伴侣定义了记忆T细胞的表观遗传景观。我们的新初步数据进一步表明在体外T细胞激活后TCF-1表达会导致染色质可及性的增长在亲梅里基因。但是，尚不清楚TCF-1在T细胞中是否对感染产生反应可以创建记忆T细胞的表观遗传认同。针对目标所需的TCF-1域染色质及其潜在的合作因素也尚不清楚。 TCF-1如何依赖于需要定义与促记忆基因相关的表观基因组。要回答这些问题，我们将审问 TCF-1及其潜在伴侣对CD8+ T细胞在体外的可及性的影响。使用最先进的工具，我们将生成依赖TCF-1的3D基因组组织的地图定义表观基因组的变化与记忆基因相关。我们将在体内进一步翻译这些发现利用单细胞表观基因组学，转录组和流式细胞仪测定法。预期的结果提案是对TCF-1和染色质之间基本相互作用的详细理解外围T细胞可以探索以设计组合疗法，包括表观遗传编辑选择性地改变T细胞命运。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Remodeling the chromatin landscape in T lymphocytes by a division of labor among transcription factors.

DOI：
10.1111/imr.12942
发表时间：
2021-03
期刊：
Immunological reviews
影响因子：
8.7
作者：
Vahedi G
通讯作者：
Vahedi G

TCF-1 promotes chromatin interactions across topologically associating domains in T cell progenitors.

DOI：
10.1038/s41590-022-01232-z
发表时间：
2022-07
期刊：
NATURE IMMUNOLOGY
影响因子：
30.5
作者：
Wang, Wenliang;Chandra, Aditi;Goldman, Naomi;Yoon, Sora;Ferrari, Emily K.;Nguyen, Son. C.;Joyce, Eric F.;Vahedi, Golnaz
通讯作者：
Vahedi, Golnaz

Assessment of network module identification across complex diseases