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 associated enhancers. 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL095783-06
Application #
9446502
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2010-01-01
Project End
2022-04-30
Budget Start
2018-06-01
Budget End
2019-04-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Genetics
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Sun, Qianchuang; Liu, Shuyan; Liu, Kexiang et al. (2018) Role of Semaphorin Signaling During Cardiovascular Development. J Am Heart Assoc 7:
Peng, Yin; Yan, Shun; Chen, Dongquan et al. (2017) Pdgfrb is a direct regulatory target of TGF? signaling in atrioventricular cushion mesenchymal cells. PLoS One 12:e0175791
Peng, Yin; Song, Lanying; Li, Ding et al. (2016) Sema6D acts downstream of bone morphogenetic protein signalling to promote atrioventricular cushion development in mice. Cardiovasc Res 112:532-542
Yan, Shun; Jiao, Kai (2016) Functions of miRNAs during Mammalian Heart Development. Int J Mol Sci 17:
Peng, Yin; Song, Lanying; Li, Ding et al. (2016) Sema6D acts downstream of bone morphogenetic protein signalling to promote atrioventricular cushion development in mice. Cardiovasc Res :
Chen, Dongquan; Li, Yufeng; Wang, Lizhong et al. (2015) SEMA6D Expression and Patient Survival in Breast Invasive Carcinoma. Int J Breast Cancer 2015:539721
Liu, Yuelong; Harmelink, Cristina; Peng, Yin et al. (2014) CHD7 interacts with BMP R-SMADs to epigenetically regulate cardiogenesis in mice. Hum Mol Genet 23:2145-56
Peng, Yin; Song, Lanying; Zhao, Mei et al. (2014) Critical roles of miRNA-mediated regulation of TGF? signalling during mouse cardiogenesis. Cardiovasc Res 103:258-67
Harmelink, Cristina; Peng, Yin; DeBenedittis, Paige et al. (2013) Myocardial Mycn is essential for mouse ventricular wall morphogenesis. Dev Biol 373:53-63
Peng, Yin; Zhao, Shaomin; Song, Langying et al. (2013) Sertad1 encodes a novel transcriptional co-activator of SMAD1 in mouse embryonic hearts. Biochem Biophys Res Commun 441:751-6

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