Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease

Xiao，Feng1; Zhang，Xiaoran1; Morton，Sarah U.2,3; Kim，Seong Won4; Fan，Youfei5; Gorham，Joshua M.4; Zhang，Huan6; Berkson，Paul J.1; Mazumdar，Neil1; Cao，Yangpo1,13; Chen，Jian1; Hagen，Jacob7; Liu，Xujie1; Zhou，Pingzhu1; Richter，Felix7; Shen，Yufeng8; Ward，Tarsha4; Gelb，Bruce D.7,9; Seidman，Jonathan G.4; Seidman，Christine E.4,10,11; Pu，William T.1,12

2024-03-01

10.1038/s41588-024-01669-y

Nature Genetics   影响因子和分区

1061-4036

1546-1718

Rare coding mutations cause ∼45% of congenital heart disease (CHD). Noncoding mutations that perturb cis-regulatory elements (CREs) likely contribute to the remaining cases, but their identification has been problematic. Using a lentiviral massively parallel reporter assay (lentiMPRA) in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we functionally evaluated 6,590 noncoding de novo variants (ncDNVs) prioritized from the whole-genome sequencing of 750 CHD trios. A total of 403 ncDNVs substantially affected cardiac CRE activity. A majority increased enhancer activity, often at regions with undetectable reference sequence activity. Of ten DNVs tested by introduction into their native genomic context, four altered the expression of neighboring genes and iPSC-CM transcriptional state. To prioritize future DNVs for functional testing, we used the MPRA data to develop a regression model, EpiCard. Analysis of an independent CHD cohort by EpiCard found enrichment of DNVs. Together, we developed a scalable system to measure the effect of ncDNVs on CRE activity and deployed it to systematically assess the contribution of ncDNVs to CHD.

SCI

英语

其他

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)[20POST35200226] ; AHA["2U01HL098147","U01 HL098166"] ; Boston Children's Hospital Office of Faculty Development[EEC-1647837]

Genetics & Heredity

Genetics & Heredity

WOS:001166656000001

NATURE PORTFOLIO

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85185323631

Scopus

1.Department of Cardiology,Boston Children’s Hospital,Boston,United States
2.Department of Pediatrics,Harvard Medical School,Boston,United States
3.Division of Newborn Medicine,Boston Children’s Hospital,Boston,United States
4.Department of Genetics,Harvard Medical School,Boston,United States
5.Department of Pediatrics,Shandong Provincial Hospital Affiliated to Shandong First Medical University,Jinan,China
6.Department of Radiation Oncology,Dana–Farber Cancer Institute,Boston,United States
7.Mindich Child Health and Development Institute and Department of Pediatrics,Icahn School of Medicine at Mount Sinai,New York City,United States
8.Departments of Systems Biology and Biomedical Informatics,Columbia University Medical Center,New York City,United States
9.Department of Genetics and Genomic Sciences,Icahn School of Medicine at Mount Sinai,New York City,United States
10.Division of Cardiology,Brigham and Women’s Hospital,Boston,United States
11.Howard Hughes Medical Institute,Chevy Chase,United States
12.Harvard Stem Cell Institute,Cambridge,United States
13.Department of Pharmacology,School of Medicine,Southern University of Science and Technology,Shenzhen,China

Xiao，Feng,Zhang，Xiaoran,Morton，Sarah U.,et al. Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease[J]. Nature Genetics,2024,56(3):420-430.

Xiao，Feng.,Zhang，Xiaoran.,Morton，Sarah U..,Kim，Seong Won.,Fan，Youfei.,...&Pu，William T..(2024).Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease.Nature Genetics,56(3),420-430.

Xiao，Feng,et al."Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease".Nature Genetics 56.3(2024):420-430.