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Direct Epigenetic Reprogramming of T Cells

T 细胞的直接表观遗传重编程

基本信息

批准号：
8955075
负责人：
Artem Barski
金额：
$ 234万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8955075
关键词：
Affect Allergens Area Asthma Autoimmunity Back Beryllium Blood CD4 Positive T Lymphocytes Cell Lineage Cells Chimeric Proteins Chromatin Communicable Diseases DNA Binding Domain DNA Methylation Deposition Elements Engineering Enzymes Epigenetic Process Genes Helminths Helper-Inducer T-Lymphocyte Heterogeneity Human Hypersensitivity IL4 gene Immune Immune System Diseases Immune response Immunosuppressive Agents Immunotherapy Infection Inflammatory Knowledge Lead Learning Maintenance Memory Methylation Modeling Mus Mycoses Patients Phenotype Population Recording of previous events Regulatory Element Regulatory T-Lymphocyte Rest T memory cell T-Lymphocyte Technology Testing Th1 Cells Th2 Cells Tumor Antigens Work base cancer immunotherapy cytokine disease phenotype epigenetic regulation epigenome histone modification human disease interest memory CD4 T lymphocyte mouse model novel novel strategies pathogen public health relevance tool tumor

项目摘要

DESCRIPTION (provided by applicant): The heterogeneity within the CD4+ effector/memory T-cell compartment is critical for our ability to deal with diverse pathogens. For example, dedicated populations of CD4+ T helper cells are required for promoting immune defense against intracellular infections (Th1 cells), helminth infections (Th2 cells), and fungal infection (Th17 cells). On the other hand, each of these differentiated states is associated with human disease: Th1 and Th17 cells can promote autoimmunity, while Th2 cells can promote allergy and asthma. Thus, understanding and learning to exploit the mechanisms that underlie lineage choice is vital for understanding and treatment of immunological and infectious diseases. We are interested in epigenetic regulation of T-cell lineage commitment and T-cell memory. Here, we propose a novel strategy to target the Th cell epigenome in order to modify their phenotype and promote or inhibit inflammatory immune response. The cellular epigenome, represented by DNA methylation, histone modifications and ncRNA, is believed to reflect the differentiation history of the cell and determine its phenotype. Working with human helper T cells, we have found that the ability of memory CD4 T cells to quickly induce key cytokines (rapid recall ability) is correlated with epigenetic gene poising: the presence of positive histone modifications at several regulatory elements in the resting memory cells. Based on this observation, we hypothesize that memory T-cell lineage commitment is encoded in the epigenome. As a first step toward proving this hypothesis (and to T-cell reprogramming), we will attempt to modify T cell phenotype by changing chromatin marks at several key elements that we and others have previously identified. To do so, we are using TALEMs - fusion proteins of TAL-based engineered DNA binding domains (DBDs) with Epigenetic Modifier enzymes. We will use TALEMs to remove positive chromatin marks (e.g., H3K4 methylation) from the previously identified regulatory elements in the IL4/13 locus to test whether the presence of such marks is indeed required for the maintenance of Th2 phenotype and IL4/13 gene inducibility. We will also test whether deposition of negative marks (e.g., K9me2 and DNA methylation) there will be sufficient to reverse Th2 differentiation. Similarly, we will test whether deposition of the positie marks at these elements is sufficient to force Th2 cytokine inducibility in naïve T cells. Finallywe will test, whether such epigenetic reprogramming can affect disease phenotype in a mouse model of experimental asthma. If successful, this strategy may potentially lead to creation of therapies for immunological diseases and immunotherapy of cancer. In one hypothetical scenario, for asthma, allergen- specific inflammatory Th2 cells could be purified from patient's blood using tetramers, propagated and reprogrammed into immunosuppressive Tregs. These Treg cells could then be returned back to patient to restore tolerance and, potentially, to provide a cure. Importantly, the ability of allergen-specific Tregs to cure experimental asthma has already been demonstrated in a murine model. Similarly, tumor antigen-specific Treg cells could be purified from tumors and reprogrammed into Th1 effectors for immunotherapy. Knowledge gained through this study would enable similar applications in other biomedical areas.

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chromatin Preparation from Murine Eosinophils for Genome-Wide Analyses.

从鼠嗜酸性粒细胞中制备染色质用于全基因组分析。

DOI：
10.1007/978-1-4939-7896-0_20
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Bouffi,Carine;Barski,Artem;Fulkerson,PatriciaC
通讯作者：
Fulkerson,PatriciaC

RNF8 and SCML2 cooperate to regulate ubiquitination and H3K27 acetylation for escape gene activation on the sex chromosomes.

DOI：
10.1371/journal.pgen.1007233
发表时间：
2018-03
期刊：
PLoS genetics
影响因子：
4.5
作者：
Adams SR;Maezawa S;Alavattam KG;Abe H;Sakashita A;Shroder M;Broering TJ;Sroga Rios J;Thomas MA;Lin X;Price CM;Barski A;Andreassen PR;Namekawa SH
通讯作者：
Namekawa SH

Polycomb directs timely activation of germline genes in spermatogenesis.

DOI：
10.1101/gad.302000.117
发表时间：
2017-08-15
期刊：
Genes & development
影响因子：
10.5
作者：
Maezawa S;Hasegawa K;Yukawa M;Sakashita A;Alavattam KG;Andreassen PR;Vidal M;Koseki H;Barski A;Namekawa SH
通讯作者：
Namekawa SH

Analysis of ChIP-Seq and RNA-Seq Data with BioWardrobe.

使用 BioWardrobe 分析 ChIP-Seq 和 RNA-Seq 数据。