CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of
growth/development, Genital abnormalities and Ear anomalies) is a severe developmental disorder affecting
multiple organs. Congenital heart diseases are major clinical features of CHARGE syndrome, affecting >75%
of patients. More than 70% of all CHARGE cases are caused by the haploinsufficiency of CHD7, a gene that
encodes an ATP-dependent chromatin remodeling factor. The major goal of this project is to reveal the
functions of CHD7 during heart development and therefore provide mechanistic insights into the birth defects
caused by mutations in CHD7.
We recently identified CHD7 as an embryonic heart interaction partner of SMADs1, 5, and 8
(SMADs1/5/8), which are BMP receptor-activated SMADs. We further showed that CHD7 is required for
normal expression of Nkx2.5, a core cardiogenic transcription factor downstream of BMP signaling. Thus, our
study provided the first evidence implicating CHD7 as a direct epigenetic regulator of cardiogenic genes.
Currently, the functions and molecular activities of CHD7 during heart development remain largely elusive,
presenting a major barrier for understanding the developmental basis for the heart defects in CHARGE
patients. We hypothesize that CHD7 regulates the epigenetic architecture of crucial cardiogenic genes to
promote normal heart development in mammals. Two specific aims are proposed to test this hypothesis. In the
1st aim, we will reveal the regulatory target network of CHD7 in cardiomyocytes derived from the second heart
field (SHF) and examine how CHD7 is specifically loaded onto its target sites. In the 2nd aim, we will test the
role of CHD7 in recruiting histone methyltransferase to promote methylation of histone H3 lysine 4 at its
Accomplishing the proposed studies will not only greatly advance our knowledge of the tissular-,
cellular- and molecular- activities of CHD7 in developing hearts, but also will provide us with crucial clues
regarding how an epigenetic regulator acts coordinately with other genetic/epigenetic regulators to promote
normal cardiogenesis in mammals. Information obtained from our research will be invaluable for understanding
the mechanisms underlying the heart defects observed in CHARGE syndrome patients.