EPIGENETIC CONTROL OF HUMAN NEURAL CREST FORMATION: IMPACT ON NEUROCRISTOPATHIES

描述（由申请人提供）：神经嵴发育缺陷是导致大量先天性畸形的原因，通常称为神经嵴畸形，这是一些最常见的出生缺陷和遗传疾病的原因。其中神经嵴衍生组织发育不良、畸形或缺失的神经损伤包括先天性巨结肠、Treacher柯林斯、CHARGE和DiGeroge Syndrome。CHARGE综合征由染色质重塑酶CHD 7的单倍不足引起，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，患有B rjeson-Forssman- Lehmann Syndrome（BFLS）的患者有几个与CHARGE相反的特征。BFLS是由PHF 6功能丧失引起的，PHF 6是与CHD 7相互作用的染色质标记的潜在阅读器。由于PHF 6和CHD 7在发育中的神经板中存在于一个复合体中，但当丢失时具有相反的结果，因此我们假设PHF 6可能是CHD 7功能和NCC形成或增殖的负调节剂。我们的研究意义重大，因为它将为拯救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表型变异的潜在原因。此外，PHF 6是所有癌症中前64个显著突变的基因之一，CHD 7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剂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，并且结合了多学科技术，包括我们开发的脊椎动物模型。在目的1中，我们将确定PHF 6在体外和体内神经嵴发育中的作用。在目标2中，我们将确定PHF 6与CHD 7和染色质在发育中的人类神经嵴细胞中的分子基础。目的3：研究PHF 6和CHD 7在染色质上的相互作用机制，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.