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The role of Tet1 in myofibroblast differentiation

Tet1在肌成纤维细胞分化中的作用

基本信息

批准号：
10201053
负责人：
SEM H PHAN
金额：
$ 60.64万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10201053
关键词：
Achievement Address Alveolar Appearance Area Base Excision Repairs Binding Binding Proteins Biological Cell Differentiation process Cell division Cells Complex CpG Islands DNA DNA Methylation DNA Modification Methylases DNA Sequence Data Derivation procedure Development Developmental Biology Differentiation Antigens Dioxygenases Disease Elements Epigenetic Process Epithelial Cells Extracellular Matrix Fibroblasts Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Hour Impaired healing Impairment In Vitro Light Lung Malignant Neoplasms Mediating Mesenchymal Differentiation Molecular Myofibroblast Neoplasm Metastasis Process Protein Isoforms Proteins Proteomics Regulation Role Signal Pathway Smooth Muscle Actin Staining Method Specificity Stimulus Testing Tetanus Helper Peptide Thymine DNA Glycosylase Time Transgenic Mice angiogenesis base carcinogenesis cell type cytokine demethylation epigenetic regulation epigenomics healing in vivo organ growth overexpression oxidation programs promoter recruit repaired response stem cells tissue injury tissue repair transcription factor tumor growth wound

项目摘要

Project Summary: Myofibroblasts are differentiated mesenchymal cells with identified roles in development, cancer, tissue repair/remodeling. Regulation of myofibroblast differentiation involves multiple signaling pathways and respective downstream transcription factors as well as significant modulation by epigenetic factors such as DNA methylation. Abundant studies focused on identification of transcription factors and their role in regulation of the α-smooth muscle actin (Acta2) gene as a marker of differentiation, but the mechanism of epigenetic regulation is not as well understood. Select CpG islands in the Acta2 gene are differentially methylated in myofibroblasts vs. fibroblasts and epithelial cells. Impairment of DNA methylation enhances differentiation while the converse inhibits differentiation. Active demethylation by the Tet (Ten-eleven translocation) proteins, which are methylcytosine dioxygenases, is implicated in cell differentiation. Their importance in cell differentiation is suggested in studies of embryonal and other stem cells, but their significance in regulation of myofibroblast differentiation is unknown. Preliminary data showed selective induction of Tet1 and not the other 2 isoforms (Tet2 and Tet3) in myofibroblast differentiation, while Tet1 deficiency caused impaired differentiation both in vivo and in vitro. Thus the selective importance of the Tet1 isoform is suggested in differentiation. While Tet1 does not globally regulate all genes by demethylation, the identity of at least one Tet1 regulated target gene, Acta2 could be inferred from the preliminary data. Based on the previous findings and preliminary data we hypothesized that Tet1 importantly regulates myofibroblast differentiation by demethylation of regulatory DNA sequences in select target genes essential for the differentiation process. Select recruitment to the relevant target DNA sequences is mediated by Tet1 binding proteins/transcription factors with binding specificity for these DNA regions. To test this hypothesis the Specific Aims are as follows, 1) to screen for and identify Tet1 target genes important in myofibroblast differentiation in fibroblasts, 2) to study the mechanism of Tet1 regulation of key target genes essential for myofibroblast differentiation, and 3) to assess the in vivo significance of Tet1 regulation of myofibroblast differentiation. The studies will use epigenomic approaches to assess differentially methylated genes and transgenic mice to evaluate the biological importance of Tet1 and select differentiation relevant genes in specific cell types in vivo. Achievement of the goals will shed new light on the epigenetic regulation of myofibroblast differentiation of relevance to development, cancer and tissue repair/remodeling.

项目总结: