KLF-mediated coordination of signaling and epigenetic mechanisms in the skin

KLF 介导的皮肤信号传导和表观遗传机制的协调

• 批准号: 10553658
• 负责人: Sarah E. Millar
• 金额: $ 37.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553658
• 关键词: ATAC-seq; Address; Affect; Basal cell carcinoma; Binding; Binding Sites; Biochemical; Biological Assay; Cell Fate Control; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Collaborations; Communication; Complex; Data; Data Set; Disease; Enhancers; Epidermis; Epigenetic Process; Epithelial Cells; FOXC1 gene; FOXP1 gene; Failure; Family member; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic approach; Growth; HDAC1 gene; HDAC3 gene; Hair; Hair follicle structure; Hair shaft structure; Histone Acetylation; Histone Deacetylase; Intestines; LGR5 gene; Ligation; Malignant Epithelial Cell; Mediating; Nuclear; Nucleosomes; Output; Overlapping Genes; Peptide Initiation Factors; Process; Proliferating; Regulator Genes; Reporter; Repression; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Squamous cell carcinoma; TCF3 gene; TCF7L2 gene; Testing; WNT Signaling Pathway; beta catenin; cell type; derepression; epidermal stem cell; experimental study; fibroblast growth factor 18; gene interaction; induced pluripotent stem cell; intestinal epithelium; mouse model; mutant; novel; novel therapeutic intervention; novel therapeutics; premature; promoter; recruit; regenerative; response; skin disorder; stem cell function; stem cells; transcription factor; transcriptome sequencing

Project Summary Regenerative processes in the skin require cross-talk of multiple cell signaling and epigenetic mechanisms; failure of this communication leads to a range of diseases from skin cancers to hair loss conditions. Delineating how these inputs are coordinated to impact gene expression at the level of chromatin has potential to identify novel therapies for skin dysfunction. Pioneer transcription factors initiate gene expression by binding nucleosome-enriched silent chromatin and recruiting chromatin modifiers to provide access for transcription machinery. Key regulatory genes in hair follicle stem cells are associated with “super enhancers” containing binding sites for multiple transcription factors, suggesting that transcription factors activated in response to diverse signals collaborate with each other and with chromatin modifiers to coordinate cell-type specific transcriptional output. KLF4, a Krüppel-like family member, has well-established functions as a pioneer transcription factor in iPS reprogramming, blocks Wnt/β-catenin signaling in intestinal epithelial cells, is required for normal differentiation of interfollicular epidermis, and is highly expressed in hair follicle stem cells. Opposite to KLF4, KLF5 promotes basal epidermal proliferation, and is required for Wnt/β-catenin signaling in intestine. KLF4 and KLF5 can directly repress each other's expression and KLF5 is absent from quiescent hair follicle stem cells, but is expressed in hair follicle matrix cells and in differentiating hair shaft cortex precursors that are highly Wnt-active. The Aims of this proposal are: (1) to test the hypothesis that KLF4 integrates multiple signals to maintain hair follicle stem cell quiescence by (i) directly activating hair follicle stem cell quiescence genes, and (ii) complexing with TCF3/TCF4/HDAC to suppress Wnt targets; (2) to test the hypothesis that mutually antagonistic KLF4 and KLF5 functions control key transitions of hair follicle stem cells and their progeny. Genetic mouse models, and biochemical and genomics approaches will be used to address these questions.

项目摘要 皮肤的再生过程需要多种细胞信号和表观遗传机制的相互作用； 这种沟通的失败会导致一系列疾病，从皮肤癌到脱发。划定 如何协调这些输入以影响染色质水平上的基因表达有可能确定 治疗皮肤功能障碍的新疗法。先锋转录因子通过结合启动基因表达 富含核小体的沉默染色质和招募染色质修饰物为转录提供通道 机械设备。毛囊干细胞中的关键调控基因与包含 多个转录因子的结合位点，表明转录因子在响应于 不同的信号相互协作，并与染色质修饰物一起协调特定的细胞类型 转录输出。KLF4，一个像Krüppel一样的家庭成员，具有公认的先驱功能 IPS重编程中的转录因子，阻断肠上皮细胞中的Wnt/β-catenin信号 是毛囊间表皮正常分化所必需的，在毛囊干细胞中高表达。 与KLF4相反，KLF5促进基底表皮的增殖，是Wnt/β-catenin信号转导所必需的。 肠子。KLF4和KLF5可以直接抑制彼此的表达，静止的头发中不存在KLF5 毛囊干细胞，但在毛囊基质细胞和分化的毛干皮质前体细胞中表达 它们是高度活跃的WNT。这一建议的目的是：(1)检验KLF4整合的假设 通过(I)直接激活毛囊干细胞维持毛囊干细胞静止的多种信号 静息基因，以及(Ii)与TCF3/TCF4/HDAC络合抑制Wnt靶点；(2)检测 相互拮抗的KLF4和KLF5功能控制毛囊干细胞关键转变的假说 以及它们的后代。将使用遗传小鼠模型以及生化和基因组学方法来解决 这些问题。