The role of Foxp1/2/4 mediated chromatin remodeling in skin and hair follicle dev

Foxp1/2/4 介导的染色质重塑在皮肤和毛囊发育中的作用

• 批准号: 8294905
• 负责人: EDWARD E MORRISEY
• 金额: $ 6.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8294905
• 关键词: Adult; Affect; Basal Cell; Cardiovascular system; Cell Differentiation process; Cell Lineage; Cell physiology; Chromatin Remodeling Factor; DBL Oncoprotein; DNA Binding; DNA Sequence; Data; Defect; Development; Disease; Epigenetic Process; Event; Failure; Foxes; Gene Family; Gene Targeting; Genes; Genetic Transcription; HDAC1 gene; HDAC2 gene; Hair; Hair follicle structure; Heart; Histone Deacetylase; Homeostasis; Knock-out; Knockout Mice; Lead; Lung; Mediating; Molecular; Mus; Mutant Strains Mice; NuRD complex; Pathway interactions; Pattern; Play; Pluripotent Stem Cells; Population; Regulation; Repression; Role; Skin; Skin Cancer; Stem cells; System; Tissues; base; cell type; chromatin remodeling; embryonic stem cell; gene repression; in vivo; loss of function; lung development; member; novel; recombinase; research study; self-renewal; skin lesion; stem; stem cell population; transcription factor

Recent evidence has shown that alterations in epigenetic states can alter the ability of stem cell populations to differentiate into specific cell lineages and in some circumstances lead to the de-differentiation of differentiated cell types into more pluripotent stem cells. The molecular pathways controlling such epigenetic/chromatin remodeling events are still unclear. The forkhead or Fox gene family of transcriptional regulatory factors regulate tissue specific gene transcription and are important for self-renewal and differentiation of stem/progenitor cell populations during development. We have shown that the Foxp1/2/4 subfamily of Fox factors are highly expressed in developing skin and hair follicles. Recent evidence from our lab as well as others demonstrated that Foxp1/2/4 and the related Foxp3 factor interact with chromatin remodeling complexes, including NuRD and NCoR to repress gene specific expression during cell differentiation. Evidence from our lab shows that Foxp1/2/4 interact with components of the NuRD complex, mediating transcriptional repression of important target genes in the lung and heart. Our preliminary data suggest that Foxp1/2/4-NuRD interactions have profound affects on lung development as demonstrated by defects in Foxp1-HDAC2 and Foxp2-HDAC2 compound mutant mice. These studies illustrate one of the few examples of the chromatin remodeling complex NuRD interacting with a sequence specific DNA binding transcription factor. Given these fundamental roles for Foxp1/2/4 in development of the cardiovascular and pulmonary systems, we predict that they will play a similarly critical role in regulation of hair follicle development. To explore the role of Foxp1/2/4 in skin and hair follicle development, we propose to 1) determine the roles for Foxp1/2/4 in skin and hair follicle development by deleting these genes in epidermal specific knockout mice and 2) Determine the roles for HDAC1/2 in skin and hair follicle development through in vivo loss of function analyses.

最近的证据表明，表观遗传状态的改变可以改变干细胞群体分化为特定细胞谱系的能力，并且在某些情况下导致分化的细胞类型去分化为更具多能性的干细胞。控制这种表观遗传/染色质重塑事件的分子途径仍然不清楚。转录调节因子的叉头或Fox基因家族调节组织特异性基因转录，并且对于自我更新和 干/祖细胞群在发育过程中的分化。我们已经证明Fox因子的Foxp 1/2/4亚家族在发育中的皮肤和毛囊中高度表达。我们实验室以及其他实验室的最新证据表明，Foxp 1/2/4和相关Foxp 3因子与染色质重塑复合物（包括NuRD和NCoR）相互作用，以抑制细胞分化过程中的基因特异性表达。来自我们实验室的证据表明，Foxp 1/2/4与NuRD复合物的组分相互作用，介导肺和心脏中重要靶基因的转录抑制。我们的初步数据表明，Foxp 1/2/4-NuRD相互作用对肺发育有深远的影响，如Foxp 1-HDAC 2和Foxp 2-HDAC 2复合突变小鼠中的缺陷所证明的。这些研究阐明了染色质重塑复合物NuRD与序列特异性DNA结合转录因子相互作用的少数例子之一。鉴于Foxp 1/2/4在心血管和肺系统发育中的这些基本作用，我们预测它们将在毛囊调节中发挥类似的关键作用。 发展为了探索Foxp 1/2/4在皮肤和毛囊发育中的作用，我们建议1）通过在表皮特异性敲除小鼠中删除Foxp 1/2/4基因来确定Foxp 1/2/4在皮肤和毛囊发育中的作用; 2）通过体内功能丧失分析来确定HDAC 1/2在皮肤和毛囊发育中的作用。