Epigenetic Regulation of Skin Regional Specificity

皮肤区域特异性的表观遗传调控

• 批准号: 10660750
• 负责人: Cheng-Ming Chuong
• 金额: $ 54.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660750
• 关键词: 3-Dimensional; ATAC-seq; Affect; Alopecia; Anterior; Architecture; Birds; Cell Communication; Cells; ChIP-seq; Chickens; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Color; Communication; Competence; Data; Dermal; Dermis; Development; Dorsal; Ear; Epidermis; Epigenetic Process; Epithelium; Evaluation; Exhibits; Experimental Models; Face; Feathers; Fibroblast Growth Factor; Fibroblasts; Future; Gene Cluster; Gene Expression Regulation; Genetic Recombination; Genetic study; Genome; Hair; Human; Knowledge; Learning; Mediating; Mesenchymal; Modeling; Molecular; Morphogenesis; Morphology; Mus; Narration; Neural Crest; Organizational Change; Organoids; Patients; Phenotype; Polishes; Production; Regenerative Medicine; Regulation; Research; Role; Scalp structure; Signal Transduction; Skin; Skin Substitutes; Skin injury; Specific qualifier value; Specificity; Specimen; Tail; Technology; Time; Tissue Transplantation; Transplantation; Untranslated RNA; Variant; Viral; Work; antagonist; appendage; combinatorial; craniofacial; epigenetic regulation; experimental study; genetic analysis; genome-wide; insight; member; molecular scale; morphogens; progenitor; single cell analysis; skin regeneration; stem cell biology; stem cells; transcriptome; transcriptome sequencing

Summary (30 lines) The long-term objective of our research is to understand the basic principles regulating the development and regeneration of skin and its appendages, and to apply this knowledge to regenerative medicine. Recent progress in stem cell biology has allowed the production of skin substitutes which help patients suffering from severe skin injuries to survive. Yet, these skin substitutes lack regional specificities seen in human skin (e.g., scalp, face, palm, sole). The next major challenge will be to produce skins with proper region-specific phenotypes for optimal function. While studies on region-specific skin in the mouse ear, sole and human fibroblasts were carried out, no systemic studies have been made. Birds exhibit remarkable region-specific skin appendages for communication, endothermy and flight, and are accessible to experimentation. We have demonstrated how temporo-spatial expression of diffusible morphogens (Wnt, FGF, BMP and their antagonists) can mediate epidermal-dermal interactions to generate distinct skin appendage phenotypes. Yet, how these morphogens work at the epigenetic level, including upstream in the dermis and downstream in the epidermis, are mostly unknown. Several recent studies provide new clues. First, the scalp is known to be a unique skin domain with distinct appendage phenotypes in humans (terminal hairs or alopecia) and birds (crest feathers or combs). Polish chicken variants grow feathers instead of the comb on the scalp. Using genetic analyses, we showed a195 bp duplication in the non-coding region of HoxC10. This study offers new clues to study how misexpression of HoxC members can act on morphogens to change combs into feathers, and how the HoxC gene cluster is regulated. Second, using transcriptome analyses to compare dorsal and shank skin, we recently identified a group of molecular scale-feather converters. Following this clue, we performed ATAC- seq and high-order chromatin interactome studies to explore 3D genome organizations in feathers, scales, and intermediate specimens. Preliminary data reveal differential chromatin accessible regions in feather / scale inductive dermis, and in competent / committed epidermis, providing new insights into the induction of region- specific skin appendages. Thus, the time is ripe to follow these clues to advance our understanding of skin regional specification. We hypothesize that dermis in different skin regions exhibit distinct epigenetic profiles, leading to specific combinatorial morphogen expressions, which guide epidermis to form specific appendage types. In development, epidermal cells, during a time window, can exhibit bipotent competency to respond to different dermal signals and form specific appendage types. The hypothesis will be evaluated and developed further using a combination of classical tissue transplantation experiments and cutting-edge omics technologies. We will focus on the scalp, dorsal and shank skins in this study but consider the fundamental principles that would be applicable to other skin regions. The work will advance our understanding of how region-specific skin appendages are established from the morphogen level to the epigenetic level.

摘要（30行） 我们研究的长期目标是了解规范发展的基本原则， 皮肤及其附属物的再生，并将这些知识应用于再生医学。最近 干细胞生物学的进步使得皮肤替代品的生产成为可能， 严重的皮肤损伤才能活下来然而，这些皮肤替代品缺乏在人类皮肤中看到的区域特异性（例如， 头皮、面部、手掌、脚底）。下一个主要的挑战将是生产皮肤与适当的区域特定 表型的最佳功能。对小鼠耳、足底和人的区域特异性皮肤的研究 进行了成纤维细胞，没有进行系统性研究。鸟类具有显著的区域特异性皮肤 通信，恒温和飞行的附件，并可用于实验。我们有 证明了扩散性形态发生素（Wnt、FGF、BMP及其受体）的时空表达是如何影响细胞增殖的。 拮抗剂）可以介导表皮-真皮相互作用以产生不同的皮肤附属物表型。然而， 这些形态发生素如何在表观遗传水平上起作用，包括真皮的上游和 表皮，大部分是未知的。最近的几项研究提供了新的线索。首先，头皮是已知的 在人类（终毛或脱毛）和鸟类（冠）中具有独特附属物表型的独特皮肤区域 羽毛或梳子）。波兰鸡的变种在头皮上长羽毛而不是梳子。利用遗传 分析表明，HoxC 10基因的非编码区存在195 bp的重复序列。这项研究提供了新的线索， 研究HoxC成员的错误表达如何作用于形态发生素，将梳子变成羽毛，以及如何 HoxC基因簇受到调控。第二，使用转录组分析来比较背部和小腿皮肤， 我们最近发现了一组分子尺度-羽毛转换器。根据这个线索，我们进行了ATAC- seq和高阶染色质相互作用组研究，以探索羽毛，鳞片和 中间标本。初步数据揭示了羽毛/鳞片中的差异染色质可及区域 诱导真皮，并在主管/承诺表皮，提供了新的见解诱导区域- 特殊的皮肤附属物因此，现在是时候跟随这些线索来推进我们对皮肤的理解了 区域规格我们假设不同皮肤区域的真皮表现出不同的表观遗传特征， 导致特定的组合形态发生表达，其引导表皮形成特定的附属物 类型在发育过程中，表皮细胞在一个时间窗内可以表现出双能的能力，以响应于 不同的皮肤信号和形成特定的附属物类型。该假设将被评估和发展 进一步使用经典组织移植实验和尖端组学的组合， 技术.我们将重点放在头皮，背部和小腿皮肤在这项研究中，但考虑的基本 这些原则适用于其他皮肤区域。这项工作将促进我们了解如何 从形态发生水平到表观遗传水平建立区域特异性皮肤附属物。