Mechanisms of de novo Germline Histone Mutations Underlying Developmental Disorders

项目摘要 染色质整合了环境和固有的细胞信号来协调核小体的修饰， 因此，调节对细胞正常发育的命运和身份至关重要的基本细胞功能。 沉积或去除核小体修饰的酶的突变通常会扰乱染色质结构 并导致许多人类发育障碍的病理性基因表达程序。作为基本单位 在核小体中，组蛋白基因本身的变化直到最近才在儿童中被发现 发育障碍及其机制和功能作用在很大程度上仍不清楚。给定 越来越多的组蛋白胚系突变及其影响缺乏了解，这是势在必行的 建立动物模型以阐明其生理功能并描述其潜在的机制。我的目标 是通过整合生化和基因组来揭示组蛋白突变在发育过程中的功能 通过使用动物模型进行检测，目的如下：(1)研究 组蛋白H4突变体被招募到异染色质，(2)确定组蛋白H4突变如何调节 染色质可及性和神经分化，以及(3)确定组蛋白突变在 发展。指导这一提议的中心假设是组蛋白突变改变了异染色质 沉默，影响基因表达，促进神经分化，这些都对大脑有贡献 缺陷。这项研究将对组蛋白胚系的分子机制提供新的见解。 突变和发育障碍的表观遗传学原因。在辅导期内，我将接受培训 在以下关键技能方面：获得小鼠模型专业知识，扩大我对小鼠大脑的知识 开发和体内发育障碍的大脑模型，深化赠款撰写和培训 指导，以及科学的职业发展。随着这些宝贵技能的获得，久负盛名的 Allis实验室的生化和基因组学方法，神经发生和哺乳动物的伟大培训 我的合作导师Hatten博士的大脑开发，以及我杰出的 合作者，我将以一个独特的位置应用不同的方法来研究组蛋白胚系突变 发育障碍。重要的是，我将从我的科学顾问委员会得到额外的指导， 还有来自Allis博士和Hatten博士的出色的指导，帮助我过渡到独立。一起， 这次K99/R00奖项的培训和支持将实现我成为一名独立人士的职业目标 染色质和发育生物学领域的研究员。

Project Summary Chromatin integrates environmental and intrinsic cellular cues to orchestrate nucleosome modifications, therefore regulating basic cellular functions that are essential for cell fate and identity in normal development. Mutations in enzymes that deposit or remove nucleosome modifications often dysregulate chromatin structure and result in pathological gene expression programs in many human developmental disorders. As the basic unit of the nucleosome, alterations in histone genes themselves have only been recently identified in children with developmental disorders and their mechanistic and functional roles remain largely unknown. Given the increasing number of histone germline mutations and lack of understanding of their impact, it is imperative to establish animal models to elucidate their physiological functions and delineate underlying mechanisms. My goal is to uncover the function of histone mutations during development by integrating biochemical and genomic assays, along with employing animal models through the followings aims: (1) Investigate the mechanism of how histone H4 mutants are recruited to heterochromatin, (2) Determine how histone H4 mutations regulate chromatin accessibility and neural differentiation, and (3) Identify the function of histone mutations during development. The central hypothesis guiding this proposal is that histone mutations alter heterochromatin silencing, impact gene expression, and promote neural differentiation, which altogether contribute to brain defects. This research will provide new insights into molecular mechanisms underlying histone germline mutations and the epigenetic causes of developmental disorders. During the mentored period, I will gain training in the following key skillsets: acquiring expertise in mouse models, expanding my knowledge of mouse brain development and in vivo brain models of developmental disorders, deepening training in grant writing and mentoring, as well as scientific career development. With acquisition of these valuable skills, the well-established biochemical and genomics approaches in the Allis laboratory, the great training in neurogenesis and mammalian brain development from my co-mentor Dr. Hatten, and strong support and expertise from my outstanding collaborators, I will be in a unique position to apply diverse approaches to study histone germline mutations in developmental disorders. Importantly, I will receive additional mentoring from my Scientific Advisory Committee, along with fantastic mentorship from Dr. Allis and Dr. Hatten to facilitate my transition to independence. Together, this training and support from the K99/R00 award will fulfill my career goal of becoming an independent investigator in the field of chromatin and developmental biology.