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 皮肤中的再生过程需要多个细胞信号传导和表观遗传机制的串扰。 这种交流的失败导致从皮肤癌到脱发状况的一系列疾病。描绘 这些输入如何协调以影响染色质水平的基因表达有潜力鉴定 皮肤功能障碍的新型疗法。先锋转录因子通过结合启动基因表达 富含核小体的无声染色质和募集染色质修饰剂可提供转录的访问 机械。毛囊干细胞中的关键调节基因与含有“超级增强子”有关 多种转录因子的结合位点，表明转录因子响应于 潜水员信号相互协作，并与染色质修饰符协调特定的细胞类型 转录输出。 KLF4是Krüppel的家庭成员，他作为先驱的功能良好 IPS重编程中的转录因子，阻断肠上皮细胞中的Wnt/β-catenin信号传导IS 正常分化的毛间表皮所必需，并且在毛发干细胞中高度表达。 与KLF4相反，KLF5促进了碱性表皮增殖，并且需要Wnt/β-catenin信号传导 肠。 KLF4和KLF5可以直接反映彼此的表达，而静态头发不存在KLF5 叶状干细胞，但在发膜基质细胞和分化的发轴皮层前体中表示 高度活跃。该提案的目的是：（1）检验KLF4整合的假设 多个信号通过（i）直接激活毛囊干细胞来维持毛囊干细胞的静止 静止基因，（ii）与TCF3/TCF4/HDAC络合以抑制Wnt靶标； （2）测试 假设相互拮抗的KLF4和KLF5功能控制着毛发干细胞的关键过渡 和他们的后代。遗传小鼠模型以及生化和基因组学方法将用于解决 这些问题。