Molecular Mechanisms of Cell Fate Decisions in Hair Follicle Stem Cells

毛囊干细胞细胞命运决定的分子机制

• 批准号: 7987181
• 负责人: Tudorita Tumbar
• 金额: $ 37.71万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-16 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987181
• 关键词: Ablation; Acute; Address; Adopted; Adult; Behavior; Biological Assay; Biological Models; CCL4 gene; Cell Culture Techniques; Cell Fate Control; Cell Lineage; Cell Maintenance; Cell Separation; Cell Transplantation; Cell surface; Cells; Characteristics; Chromatin; Clinic; Co-Immunoprecipitations; Cultured Cells; DNA; Data; Developmental Gene; Disease; Enzymes; Epigenetic Process; Frequencies; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genome; Genomics; Germ; Goals; Hair; Hair follicle structure; Heterogeneity; Histone H2B; Histones; Homeostasis; Immunofluorescence Immunologic; Label; Light; Link; Location; Maps; Memory; Messenger RNA; Microarray Analysis; Modeling; Molecular; Morphology; Mus; Normal tissue morphology; Nuclear; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Physiologic pulse; Population; Precipitation; Prevalence; Proliferating; Regulation; Relative (related person); Skin; Sorting - Cell Movement; Staging; Stem cells; Structure; System; Testing; Tetanus Helper Peptide; Time; Tissues; Western Blotting; Work; adult stem cell; base; cell behavior; cell type; chromatin immunoprecipitation; gene repression; genome-wide; histone modification; injured; insight; knockout gene; mRNA Expression; novel; progenitor; programs; promoter; protein complex; protein protein interaction; public health relevance; regenerative therapy; research study; self-renewal; stem cell fate; stem cell niche; stem cell population; therapeutic target; tissue regeneration; tool; transcription factor

DESCRIPTION (provided by applicant): Deciphering the molecular mechanisms of adult stem cell (SC) fate decisions is essential for understanding disease and for tissue regenerative therapy. The overall goal of this proposal is to utilize hair follicles and skin as model systems to address at the molecular level the interplay of transcriptional factors and epigenetic regulation in fate choice decisions of a vertebrate adult stem cell population in its native tissue. Because hair follicle stem cells synchronously proliferate and return to quiescence in the mouse skin, this system allows mechanistic insight that is otherwise more difficult to achieve. In Aim (1) we plan to investigate in more depth the relationship between more dormant versus more active cell subpopulations in the hair follicle stem cell niche, by characterizing their morphogenetic and self-renewal ability in cell culture and cell transplantation assays. The existence of these two kinds of cell subpopulations in stem cell niches appears to be a relatively common feature for at least several vertebrate tissues. Their interplay in maintaining tissue homeostasis is important for accurate description of stem cell behavior and fate decisions. In Aim (2) we will examine the distribution of histone marks across the genome at two stages of stem cell activity by chromatin immuno-precipitation and sequencing, and attempt to examine a potential link between two known adult tissue stem cells features: quiescence and plasticity. In Aim (3) we will employ two transcription factors Runx1 and Gata6 as fate acquisition regulators. We will test their potential implication in remodeling the stem cell histone epigenome via interactions with a battery of histone modifying enzymes we found expressed in the hair follicle in a relevant pattern. We will induce acute loss of Runx1 and Gata6 in mouse skin and examine the mRNA expression level of specific histone modifying enzymes in the relevant hair follicle cell populations. In addition we will perform co-immunoprecipitation or pull-down experiments to examine a potential direct protein-protein interaction between Runx1 or Gata6 and specific histone modifying enzymes. This will begin to address the mechanisms of fate acquisition in a vertebrate adult stem cell population and shed light on the interplay between transcription factors that work as master regulator in orchestrating cell fate and global remodeling of histone epigenetic marks. PUBLIC HEALTH RELEVANCE: A large number of diseases are due to miss-regulation of cell fate acquisition of adult tissue stem cells during their activity to maintain normal tissue homeostasis. There has been recently great promise for developing novel drug therapeutics that target specific histone modifying enzymes, some already present in clinics. This proposal seeks to utilize a versatile vertebrate model system, mouse skin and hair follicles, to gain better understanding of the interplay between histone epigenetic marks and transcription factors that control cell fate decisions in adult vertebrate stem cells.

描述（由申请人提供）：破解成体干细胞（SC）命运决定的分子机制对于理解疾病和组织再生治疗至关重要。本研究的总体目标是利用毛囊和皮肤作为模型系统，在分子水平上解决转录因子和表观遗传调控在命运选择中的相互作用