Transcriptional and epigenetic basis of lung epithelial cell fate

肺上皮细胞命运的转录和表观遗传基础

• 批准号: 10030944
• 负责人: Jichao Chen
• 金额: $ 63.56万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10030944
• 关键词: AGTR2 gene; Abbreviations; Alveolar; Belief; Binding; Binding Sites; Biology; CEBPA gene; CTNNB1 gene; Cells; ChIP-seq; Chromatin; Complement; Coupled; Data; Dependence; Embryo; Ensure; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Gene Activation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Informal Social Control; Injury; Journals; Knock-out; Knowledge; Lung; Maintenance; Measures; Mediating; Modeling; Mus; Organism; Pattern; Primitive foregut structure; Publications; Regulatory Element; Role; Rosaniline Dyes; Sendai virus; Sequence Analysis; Series; Site; Testing; Therapeutic; Three-Dimensional Imaging; Transcription Factor 3; Virus Diseases; WNT Signaling Pathway; base; cell type; combinatorial; epigenome; experience; gastrointestinal; human embryonic stem cell; human stem cells; in vivo; lung development; lung regeneration; mouse genetics; postnatal; progenitor; recruit; regenerative therapy; repaired; stem cell technology; stem cells; transcription factor; transcriptome

PROJECT SUMMARY The lung epithelium consists of diverse cell types, as the result of embryonic progenitors undergoing a series of precise cell fate decisions. Upon injury, a successful repair needs to restore the proper cell fates. Recapitulation and modulation of in vivo cell fate biology holds promise for cell-based regeneration therapy. Despite such fundamental importance and our accumulating knowledge of cell fate regulators, the epigenetic basis of lung cell fate – defined in this proposal as chromatin state and its relationship to transcription factor binding – is largely unknown, but essential for mechanistic understanding of cell fate regulators. Combining mouse genetics, genomics of both purified bulk and single cells, 3D imaging, and human stem cell technology, this proposal will test our central hypothesis that sequential and combinatorial actions of NKX2-1 and Wnt signaling transcription factors control the epigenetic maturation and maintenance of lung epithelial cell types in vivo. The proposal has the following 3 aims. (1) To test whether lung fate maintenance shifts from Wnt-dependent to NKX2-1 self- reinforcing as the lung matures. (2) To test whether NKX2-1 promotes AT1 versus AT2 cell fate as a result of recruitment by YAP/TAZ/TEAD versus CEBPA, respectively. (3) To test whether NKX2-1 primes AT2 cells for AT1 differentiation.

项目总结