Statement of Benefit to California:
Year 1We study how chromatin, the complex of DNA and protein that makes up chromosomes, influences expression of genes to produce different tissues and organs in the process of development. Human embryonic stem cells provide a useful model system that allows us to address fundamental questions about role of chromatin modification and epigenetic mechanisms in cell fate decisions governing human development and disease.
With funding from CIRM we developed a human embryonic stem cell-derived in vitro model to study the formation and differentiation of human neural crest, a transient cell population that is ectodermal in origin, but undergoes a major gene expression reprogramming to acquire a remarkably broad differentiation potential and ability to migrate throughout the body to give rise to craniofacial bones and cartilages, peripheral nervous system, and cardiac structures.
We had shown that two distinct chromatin remodelers cooperate to promote the unique epigenetic plasticity and migration of the neural crest cells. Heterozygous mutations in gene encoding one of those remodelers, CHD7, result in a complex constellation of congenital anomalies called CHARGE syndrome, a sporadic, autosomal dominant disorder occurring in about 1:8000 life birth and characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. Though our work we have elucidated for the first time the molecular mechanism underlying this relatively common, but poorly understood human syndrome, and identified novel candidates targets for genes mutated in this disease.