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中文摘要
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项目摘要 诱导多能干细胞(IPS)和组织工程的最新进展开启了 以角质形成细胞为基础的组织置换治疗隐性营养不良性表皮松解症 Bullosa(RDEB)。而我们的实验室表明,骨形态发生蛋白(BMP)和维甲酸 (RA)形态原可诱导ES/iPS来源的可移植人角质形成细胞,详细机制 对角质形成细胞分化的洞察仍然是高效组织制造的主要障碍 以及美国国立卫生研究院再生医学创新项目的目标。无RA/BMP,主调节器 P63结合,但几乎没有转录变化,突出了形态谱系的重要性 选择器交互。HiChIP分析表明RA/BMP诱导染色质构象 将染色质结合的p63连接到连接的增强子/启动子并确定 每个基因的转录专一性。通过我们新的网络转录因子(TF)推断 模型中,我们发现单一转录因子Tfap2c的强制表达可以诱导 功能角质形成细胞在缺乏RA/BMP的情况下。我们随后确定了一个分两步走的 Tfap2c启动简单的上皮景观,并诱导表达 并打开P63的额外结合位点。反过来,p63使Tfap2c图案成熟 表观遗传格局导致p63正自动调节和Tfap2c子集的关闭 结合位点,将格局转变为以p63为中心的角质形成细胞转铁蛋白网络。这些数据支持 RA/BMP通过TFAP2家族成员启动表观遗传学改变的有趣假说 这最终导致p63驱动的景观到角质形成细胞的表观遗传成熟。在这 我们的目标是通过以下方式解决我们知识中的关键差距:TFAP2的功能验证- 通过确认TFAP2对RA/BMP的必要性在表观遗传景观启动中的中心网络 介导表观遗传景观变化,决定Tfap2c对早期Tf的功能需求 网络,并定义了形态诱导的Tfap2c相互作用组;阐明了p63是如何成熟的 通过测定TFAP2和p63在角质形成细胞产生过程中的染色质景观 合作允许p63正向自动调节,确定角质形成细胞成熟是否需要p63- 依赖TFAP2抑制,完善和验证角质形成细胞的推断转铁蛋白模型 差异化。这项提案的成功完成将为我们提供对 染色质的组织分化动力学和建立详细的表观遗传学特征 使我们能够开发针对以前无法治愈的遗传性皮肤病的新型细胞疗法。
英文摘要
Project Summary Recent advances with induced pluripotent stem (iPS) cells and tissue engineering have opened the door to keratinocyte-based tissue replacement for patients with Recessive Dystrophic Epidermolysis bullosa (RDEB). While our lab has shown that bone morphogenic protein (BMP) and retinoic acid (RA) morphogens can induce ES/iPS-derived graftable human keratinocytes, detailed mechanistic insights into keratinocyte differentiation remain a major roadblock to efficient tissue manufacturing and a goal of the NIH Regenerative Medicine Innovation Project. Without RA/BMP, master regulator p63 binds but exhibits few transcriptional changes, highlighting the importance of morphogen-lineage selector interactions. HiChIP analysis shows that RA/BMP induces chromatin conformational changes that connect chromatin-bound p63 to linked enhancers/promoters and determine transcriptional specificity at each gene. Through our novel network transcription factor (TF) inference model we discovered that forced expression of a single transcription factor, TFAP2C, can induce functional keratinocytes in the absence of RA/BMP. We subsequently identified a two-step mechanism where the TFAP2C initiates the simple epithelial landscape, and induces expression of and opens additional binding sites for the p63. In turn, p63 matures the TFAP2C-patterned epigenetic landscape resulting in p63 positive autoregulation and the closing of a subset of TFAP2C binding sites, shifting the landscape to a p63-centric keratinocyte TF network. These data support the intriguing hypothesis that RA/BMP initiates epigenetic changes through TFAP2 family members that ultimately result in p63-driven epigenetic maturation of the landscape to keratinocytes. In this proposal we aim to address key gaps in our knowledge through: Functional validation of the TFAP2- centric network in epigenetic landscape initiation by confirming TFAP2 necessity for RA/BMP- mediated epigenetic landscape change, determining TFAP2C functional requirement for the early TF network, and defining the morphogen-inducible TFAP2C interactome; Elucidation how p63 matures the chromatin landscape during keratinocyte production by determining how TFAP2 and p63 cooperate to allow p63 positive autoregulation, determining if keratinocyte maturation requires p63- dependent TFAP2 repression, and completing and validating an inference TF model of keratinocyte differentiation. Successful completion of this proposal will provide deep mechanistic insights into the chromatin dynamics of tissue differentiation and establish a detailed epigenetic characterization that enables development of our novel cell therapy for a previously untreatable genetic skin disorder.
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Chromatin Dynamics During Epithelial Commitment
  • 批准号:
    9981936
  • 项目类别:
  • 资助金额:
    $8.12万
  • 财政年份:
    2019
  • 负责人:
    Anthony E Oro
  • 依托单位:
Chromatin Dynamics During Epithelial Commitment
  • 批准号:
    10808258
  • 项目类别:
  • 资助金额:
    $10.82万
  • 财政年份:
    2019
  • 负责人:
    Anthony E Oro
  • 依托单位:
Chromatin Dynamics During Epithelial Commitment
  • 批准号:
    10603314
  • 项目类别:
  • 资助金额:
    $10.82万
  • 财政年份:
    2019
  • 负责人:
    Anthony E Oro
  • 依托单位:
Chromatin Dynamics During Epithelial Commitment
  • 批准号:
    10612007
  • 项目类别:
  • 资助金额:
    $44.35万
  • 财政年份:
    2019
  • 负责人:
    Anthony E Oro
  • 依托单位:
海外基金