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.

Public Health Relevance

Defects in the development of neural crest-derived tissues are responsible for some of the most common birth defects and genetic diseases, many of which present with characteristic facial features. Here we propose to investigate the proteins that are defective in two such contrasting syndromes, CHARGE and B?rjeson- Forssman-Lehmann syndromes. Understanding how these proteins are involved in epigenetic processes has the potential to help patients with these syndromes, and to shed light on neural crest development more generally.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE024584-02
Application #
8870336
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Scholnick, Steven
Project Start
2014-07-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Asad, Zainab; Pandey, Aditi; Babu, Aswini et al. (2016) Rescue of neural crest-derived phenotypes in a zebrafish CHARGE model by Sox10 downregulation. Hum Mol Genet 25:3539-3554