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Epigenetic regulations of macrophage development

巨噬细胞发育的表观遗传调控

基本信息

批准号：
10541848
负责人：
KYUNGHEE CHOI
金额：
$ 51.67万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-20 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541848
关键词：
Acetylation Applications Grants Architecture Biological Assay Blood Cells Bypass Cell Reprogramming Cell physiology Cells ChIP-seq Chromatin Chromatin Remodeling Factor Complex Cytokine Signaling Data Defect Development Developmental Process Disease EP300 gene Embryo Epigenetic Process Erythroid Erythroid Cells Flow Cytometry Gene Expression Genes Genetic Transcription Genome Mappings Goals Hematopoietic stem cells High-Throughput Nucleotide Sequencing Histones In Vitro Knock-out Macrophage Mediating Molecular Myelogenous Myeloid Cells Myeloid Progenitor Cells Outcome Output Pathologic Processes Pathway interactions Phenotype Play Pluripotent Stem Cells Population Regenerative Medicine Regulatory Element Role SMARCA4 gene SMARCC1 gene Somatic Cell TREM2 gene Testing Tissues Transferase Transposase Work XCL1 gene Yolk Sac chromatin remodeling cytokine demethylation embryonic stem cell epigenetic regulation erythroid differentiation genetic effector genome-wide genomic locus insight knock-down novel progenitor programs proto-oncogene protein Spi-1 recruit self-renewal single-cell RNA sequencing tissue regeneration tissue repair transcription factor virtual

项目摘要

Yolk sac (YS) derived erythroid-myeloid progenitors (EMPs) provide embryos with definitive erythroid and myeloid cells that form tissue resident macrophages prior to the establishment of hematopoietic stem cell (HSCs). Molecular determinants that regulate myeloid lineage differentiation from EMPs are poorly understood. The mammalian SWI/SNF chromatin-remodeling BAF (BRG1/BRM associated factor) complex plays an important role in developmental and pathological processes. Our preliminary data indicates that deletion of Baf155 (aka Srg3 or Smarcc1), a subunit of BAF complex, in the Tie2-Cre lineage (Tie2-Cre; Baf155f/f, Baf155 CKO) leads to embryonic lethality, with defects in yolk sac macrophage differentiation. Flow cytometry showed virtually no mature myeloid cells in the yolk sac at E9.5 and E10.5. However, EMPs were present in the Baf155 CKO yolk sac. Analysis of wild type and Baf155 deficient yolk sac cells by single cell RNA sequencing revealed that while myeloid lineage master regulators, Pu.1 and Myb, were expressed in the EMP population in the absence of BAF155, expression of myeloid lineage maturation genes, such as Irf8, Csf1r, and Cx3cr1 was greatly reduced, suggesting that there might be a hierarchical relationship between PU.1 and BAF mediated chromatin remodeling in activating myeloid lineage maturation program. Unexpectedly, myeloid cytokines could rescue the differentiation defect of Baf155 deficient EMPs in culture. Examination of the chromatin accessibility at the myeloid gene loci of the rescued Baf155 CKO myeloid cells by using Assay for Transposase Accessible Chromatin with high throughput sequencing (ATAC-seq) suggested common as well as unique epigenetic changes potentially contributing to myeloid lineage rescue. From these fundamental findings, the overarching goal is to demonstrate that BAF155 mediated chromatin remodeling is required at the EMP stage for myeloid lineage differentiation to occur and that cytokines can bypass BAF155 requirements in myeloid lineage development. Particularly, we will investigate the hierarchical relationship between myeloid lineage transcription factor PU.1 and BAF155 chromatin-remodeling factor in myeloid lineage development. We will also determine the myeloid lineage program that is regulated by the PU.1-BAF155 pathway. We will investigate the role of BAF155 in permitting chromatin accessibility and chromatin states of myeloid lineage gene program. We will also investigate cytokine mediated epigenetic changes that corroborate with BAF155 function in the myeloid lineage program activation. Successful completion of the work will establish the role for chromatin remodeling, interplay between chromatin architecture and transcription factors critical for myeloid lineage differentiation. The outcome will also be instrumental for generating tissue macrophages from pluripotent stem cells or somatic cell reprogramming and function of such cells in a wide range of applications in regenerative medicine, and maneuvering tissue macrophage function required for tissue repair and regeneration or diseases.

卵黄囊（YS）衍生的红细胞-髓系祖细胞（EMPs）为胚胎提供最终的红细胞和骨髓

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy.

DOI：
10.1016/j.xcrm.2022.100896
发表时间：
2023-01-17
期刊：
Cell reports. Medicine
影响因子：
0
作者：
Subramanian M;Kabir AU;Barisas D;Krchma K;Choi K
通讯作者：
Choi K

Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity.

DOI：
10.1126/scitranslmed.abb6731
发表时间：
2021-03-03
期刊：
Science translational medicine
影响因子：
17.1
作者：
Kabir AU;Subramanian M;Lee DH;Wang X;Krchma K;Wu J;Naismith T;Halabi CM;Kim JY;Pulous FE;Petrich BG;Kim S;Park HC;Hanson PI;Pan H;Wickline SA;Fremont DH;Park C;Choi K
通讯作者：
Choi K

Requisite Chromatin Remodeling for Myeloid and Erythroid Lineage Differentiation from Erythromyeloid Progenitors.

DOI：
10.1016/j.celrep.2020.108395
发表时间：
2020-11-17
期刊：
Cell reports
影响因子：
8.8
作者：
Wu J;Krchma K;Lee HJ;Prabhakar S;Wang X;Zhao H;Xing X;Seong RH;Fremont DH;Artyomov MN;Wang T;Choi K
通讯作者：
Choi K

Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis.

DOI：
10.1371/journal.pbio.3001746
发表时间：
2023-05
期刊：
PLOS BIOLOGY
影响因子：
9.8
作者：
Barisas, Derek A. G.;Ul Kabir, Ashraf;Wu, Jun;Krchma, Karen;Kim, Minseo;Subramanian, Madhav;Zinselmeyer, Bernd H. H.;Stewart, Colin L. L.;Choi, Kyunghee
通讯作者：
Choi, Kyunghee

ER71/ETV2 Promotes Hair Regeneration from Chemotherapeutic Drug-Induced Hair Loss by Enhancing Angiogenesis.