EPIGENETIC CONTROL OF HUMAN NEURAL CREST FORMATION: IMPACT ON NEUROCRISTOPATHIES

描述（由申请人提供）：神经嵴发育缺陷导致大量先天性畸形，通常被称为神经嵴病变，这是一些最常见的出生缺陷和遗传疾病的原因。神经嵴来源组织发育不良、畸形或缺失的神经嵴病变包括Hirshsprung病、Treacher Collins病、CHARGE病和digerge综合征。CHARGE综合征是由染色质重塑酶CHD7单倍性不足引起的，是一种神经嵴形成和迁移受到不利影响的多系统疾病。有趣的是，BFLS患者有几个与CHARGE相反的特征。BFLS是由PHF6功能丧失引起的，PHF6是一种与CHD7相互作用的潜在染色质标记读取器。由于PHF6和CHD7存在于发育神经板的一个复合体中，但当丢失时结果却截然不同，我们假设PHF6可能是CHD7功能和NCC形成或增殖的负调节因子。我们的研究具有重要意义，因为它将为挽救BFLS和CHARGE的替代机制奠定基础，并阐明在这些疾病患者中观察到的潜在表型变异的原因。此外，PHF6是所有癌症中64个显著突变基因之一，CHD7重复与更大的迁移潜力和侵袭性肿瘤相关。因此，在机制水平上理解这些基因可能对癌症生物学以及在各种情况下用于细胞命运决定的表观遗传机制产生深远的影响。该研究在使用对比表型来确定表观遗传修饰因子之间的相互作用如何影响神经嵴细胞命运决定方面具有创新性，并且结合了包括我们开发的脊椎动物模型在内的多学科技术。在目的1中，我们将确定PHF6在体外和体内神经嵴发育中的作用。在Aim 2中，我们将确定PHF6与CHD7和染色质在发育的人类神经嵴细胞中的关联的分子基础。在Aim 3中，我们将确定PHF6和CHD7在染色质上相互作用的机制，以建立神经嵴特异性基因表达谱。

DESCRIPTION (provided by applicant): Defective neural crest development is responsible for a large number of congenital malformations, commonly referred to as neurocristopathies, which account for some of the most common birth defects and genetic diseases. Neurocristopathies in which neural crest-derived tissues are hypoplastic, malformed or missing include Hirshsprung disease, Treacher Collins, CHARGE and DiGeroge Syndromes. CHARGE syndrome, caused by haploinsufficiency of the chromatin-remodeling enzyme CHD7, is a multisystem disorder where neural crest formation and migration is adversely affected. Interestingly, patients with B�rjeson-Forssman- Lehmann Syndromes (BFLS) have several features that contrast with CHARGE. BFLS is caused by loss of function of PHF6, a potential reader of chromatin marks that interacts with CHD7. Because PHF6 and CHD7 exist in one complex in developing neural plate but have contrasting outcomes when lost, we hypothesize that PHF6 may be a negative regulator of CHD7 function and NCC formation or proliferation. Our research is significant because it will lay the foundation for alternative mechanisms for rescuing BFLS and CHARGE and elucidate causes underlying phenotypic variability observed in patients with these disorders. Moreover, PHF6 is one of the top 64 significantly mutated genes in all cancers and CHD7 duplications are associated with greater migration potential and aggressive tumors. Understanding these genes on a mechanistic level therefore may have a far-reaching impact on cancer biology as well as on epigenetic mechanisms utilized for cell fate decisions in various contexts. The research is innovative in using contrastive phenotypes to identify how interplay between epigenetic modifiers affects neural crest cell fate determination, as well as in its combination of multidisciplinary techniques including vertebrate models we have developed. In Aim 1, we will determine the role of PHF6 in neural crest development in vitro and in vivo. In Aim 2, we will determine the molecular basis of PHF6 association with CHD7 and chromatin in developing human neural crest cells. In Aim 3, we will determine the mechanism of PHF6 and CHD7 interaction on the chromatin to establish neural crest- specific gene expression profiles.