TY - JOUR
T1 - CHD7 interacts with BMP R-SMADs to epigenetically regulate cardiogenesis in mice
AU - Liu, Yuelong
AU - Harmelink, Cristina
AU - Peng, Yin
AU - Chen, Yunjia
AU - Wang, Qin
AU - Jiao, Kai
N1 - Funding Information:
This work was supported by a grant from National Institutes of Health (R01HL095783) awarded to K.J. C.H. was awarded with American Heart Association predoctoral fellowship (09PRE2261138).
PY - 2014/4
Y1 - 2014/4
N2 - Haploinsufficiency for CHD7, an ATP-dependent nucleosome remodeling factor, is the leading cause of CHARGE syndrome. While congenital heart defects (CHDs) are major clinical features of CHARGE syndrome, affecting >75%of patients, itremains unclear whether CHD7 can directly regulate cardiogenic genesin embryos. Our complementary yeast two-hybrid and biochemical assays reveal that CHD7 is a novel interaction partner of canonical BMP signaling pathway nuclear mediators, SMAD1/5/8, in the embryonic heart. Moreover, CHD7 associates in a BMP-dependent manner with the enhancers of a critical cardiac transcription factor, Nkx2.5, that contain functional SMAD1-binding elements. Both the active epigenetic signature of Nkx2.5 regulatory elements and its proper expression in cardiomyocytes require CHD7. Finally, inactivation of Chd7 in mice impairs multiple BMP signaling-regulated cardiogenic processes. Our results thus support the model that CHD7 is recruited by SMAD1/5/8 to the enhancers of BMP-targeted cardiogenic genes to epigenetically regulate their expression. Impaired BMP activities in embryonic hearts may thus have amajor contribution to CHDs in CHARGE syndrome.
AB - Haploinsufficiency for CHD7, an ATP-dependent nucleosome remodeling factor, is the leading cause of CHARGE syndrome. While congenital heart defects (CHDs) are major clinical features of CHARGE syndrome, affecting >75%of patients, itremains unclear whether CHD7 can directly regulate cardiogenic genesin embryos. Our complementary yeast two-hybrid and biochemical assays reveal that CHD7 is a novel interaction partner of canonical BMP signaling pathway nuclear mediators, SMAD1/5/8, in the embryonic heart. Moreover, CHD7 associates in a BMP-dependent manner with the enhancers of a critical cardiac transcription factor, Nkx2.5, that contain functional SMAD1-binding elements. Both the active epigenetic signature of Nkx2.5 regulatory elements and its proper expression in cardiomyocytes require CHD7. Finally, inactivation of Chd7 in mice impairs multiple BMP signaling-regulated cardiogenic processes. Our results thus support the model that CHD7 is recruited by SMAD1/5/8 to the enhancers of BMP-targeted cardiogenic genes to epigenetically regulate their expression. Impaired BMP activities in embryonic hearts may thus have amajor contribution to CHDs in CHARGE syndrome.
UR - http://www.scopus.com/inward/record.url?scp=84897835537&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897835537&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt610
DO - 10.1093/hmg/ddt610
M3 - Article
C2 - 24293546
AN - SCOPUS:84897835537
SN - 0964-6906
VL - 23
SP - 2145
EP - 2156
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 8
M1 - ddt610
ER -