Ming-Tao Zhao1, Ning-Yi Shao1, Shijun Hu2, Ning Ma1, Rajini Srinivasan1, Fereshteh Jahanbani1, Jaecheol Lee1, Sophia L Zhang1, Michael P Snyder2, Joseph C Wu2. 1. From the Stanford Cardiovascular Institute, Department of Medicine, Division of Cardiology, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (M.-T.Z., N.-Y.S., N.M., J.L., S.L.Z., J.C.W.); Department of Cardiovascular Surgery of the Frist Affiliated Hospital, Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu, China (S.H.); Department of Chemical and Systems Biology, Stanford University School of Medicine, CA (R.S.); and Department of Genetics, Stanford University School of Medicine, CA (F.J., M.P.S.). 2. From the Stanford Cardiovascular Institute, Department of Medicine, Division of Cardiology, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (M.-T.Z., N.-Y.S., N.M., J.L., S.L.Z., J.C.W.); Department of Cardiovascular Surgery of the Frist Affiliated Hospital, Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu, China (S.H.); Department of Chemical and Systems Biology, Stanford University School of Medicine, CA (R.S.); and Department of Genetics, Stanford University School of Medicine, CA (F.J., M.P.S.). joewu@stanford.edu mpsnyder@stanford.edu shijunhu@suda.edu.cn.
Abstract
RATIONALE: Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type-specific gene expression in the human heart. OBJECTIVE: We aimed to decipher the cell type-specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression. METHODS AND RESULTS: We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31+CD144+), cardiac progenitor cells (Sca-1+), fibroblasts (DDR2+), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type-specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type-specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression. CONCLUSIONS: Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering the epigenetic modulation of regulatory DNA elements that fine-tune spatiotemporal gene expression in human cardiac development and diseases.
RATIONALE: Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type-specific gene expression in the human heart. OBJECTIVE: We aimed to decipher the cell type-specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression. METHODS AND RESULTS: We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31+CD144+), cardiac progenitor cells (Sca-1+), fibroblasts (DDR2+), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type-specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type-specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression. CONCLUSIONS: Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering the epigenetic modulation of regulatory DNA elements that fine-tune spatiotemporal gene expression in human cardiac development and diseases.
Authors: Nathaniel D Heintzman; Rhona K Stuart; Gary Hon; Yutao Fu; Christina W Ching; R David Hawkins; Leah O Barrera; Sara Van Calcar; Chunxu Qu; Keith A Ching; Wei Wang; Zhiping Weng; Roland D Green; Gregory E Crawford; Bing Ren Journal: Nat Genet Date: 2007-02-04 Impact factor: 38.330
Authors: Sharon L Paige; Sean Thomas; Cristi L Stoick-Cooper; Hao Wang; Lisa Maves; Richard Sandstrom; Lil Pabon; Hans Reinecke; Gabriel Pratt; Gordon Keller; Randall T Moon; John Stamatoyannopoulos; Charles E Murry Journal: Cell Date: 2012-09-11 Impact factor: 41.582
Authors: Wei Xie; Matthew D Schultz; Ryan Lister; Zhonggang Hou; Nisha Rajagopal; Pradipta Ray; John W Whitaker; Shulan Tian; R David Hawkins; Danny Leung; Hongbo Yang; Tao Wang; Ah Young Lee; Scott A Swanson; Jiuchun Zhang; Yun Zhu; Audrey Kim; Joseph R Nery; Mark A Urich; Samantha Kuan; Chia-an Yen; Sarit Klugman; Pengzhi Yu; Kran Suknuntha; Nicholas E Propson; Huaming Chen; Lee E Edsall; Ulrich Wagner; Yan Li; Zhen Ye; Ashwinikumar Kulkarni; Zhenyu Xuan; Wen-Yu Chung; Neil C Chi; Jessica E Antosiewicz-Bourget; Igor Slukvin; Ron Stewart; Michael Q Zhang; Wei Wang; James A Thomson; Joseph R Ecker; Bing Ren Journal: Cell Date: 2013-05-09 Impact factor: 41.582
Authors: Marta Melé; Pedro G Ferreira; Ferran Reverter; David S DeLuca; Jean Monlong; Michael Sammeth; Taylor R Young; Jakob M Goldmann; Dmitri D Pervouchine; Timothy J Sullivan; Rory Johnson; Ayellet V Segrè; Sarah Djebali; Anastasia Niarchou; Fred A Wright; Tuuli Lappalainen; Miquel Calvo; Gad Getz; Emmanouil T Dermitzakis; Kristin G Ardlie; Roderic Guigó Journal: Science Date: 2015-05-08 Impact factor: 47.728
Authors: Anshul Kundaje; Wouter Meuleman; Jason Ernst; Misha Bilenky; Angela Yen; Alireza Heravi-Moussavi; Pouya Kheradpour; Zhizhuo Zhang; Jianrong Wang; Michael J Ziller; Viren Amin; John W Whitaker; Matthew D Schultz; Lucas D Ward; Abhishek Sarkar; Gerald Quon; Richard S Sandstrom; Matthew L Eaton; Yi-Chieh Wu; Andreas R Pfenning; Xinchen Wang; Melina Claussnitzer; Yaping Liu; Cristian Coarfa; R Alan Harris; Noam Shoresh; Charles B Epstein; Elizabeta Gjoneska; Danny Leung; Wei Xie; R David Hawkins; Ryan Lister; Chibo Hong; Philippe Gascard; Andrew J Mungall; Richard Moore; Eric Chuah; Angela Tam; Theresa K Canfield; R Scott Hansen; Rajinder Kaul; Peter J Sabo; Mukul S Bansal; Annaick Carles; Jesse R Dixon; Kai-How Farh; Soheil Feizi; Rosa Karlic; Ah-Ram Kim; Ashwinikumar Kulkarni; Daofeng Li; Rebecca Lowdon; GiNell Elliott; Tim R Mercer; Shane J Neph; Vitor Onuchic; Paz Polak; Nisha Rajagopal; Pradipta Ray; Richard C Sallari; Kyle T Siebenthall; Nicholas A Sinnott-Armstrong; Michael Stevens; Robert E Thurman; Jie Wu; Bo Zhang; Xin Zhou; Arthur E Beaudet; Laurie A Boyer; Philip L De Jager; Peggy J Farnham; Susan J Fisher; David Haussler; Steven J M Jones; Wei Li; Marco A Marra; Michael T McManus; Shamil Sunyaev; James A Thomson; Thea D Tlsty; Li-Huei Tsai; Wei Wang; Robert A Waterland; Michael Q Zhang; Lisa H Chadwick; Bradley E Bernstein; Joseph F Costello; Joseph R Ecker; Martin Hirst; Alexander Meissner; Aleksandar Milosavljevic; Bing Ren; John A Stamatoyannopoulos; Ting Wang; Manolis Kellis Journal: Nature Date: 2015-02-19 Impact factor: 69.504
Authors: Chukwuemeka G Anene-Nzelu; Mick C J Lee; Wilson L W Tan; Albert Dashi; Roger S Y Foo Journal: Nat Rev Cardiol Date: 2021-08-11 Impact factor: 32.419
Authors: Irina Shchukina; Juhi Bagaitkar; Oleg Shpynov; Ekaterina Loginicheva; Sofia Porter; Denis A Mogilenko; Erica Wolin; Patrick Collins; German Demidov; Mykyta Artomov; Konstantin Zaitsev; Sviatoslav Sidorov; Christina Camell; Monika Bambouskova; Laura Arthur; Amanda Swain; Alexandra Panteleeva; Aleksei Dievskii; Evgeny Kurbatsky; Petr Tsurinov; Roman Chernyatchik; Vishwa Deep Dixit; Marko Jovanovic; Sheila A Stewart; Mark J Daly; Sergey Dmitriev; Eugene M Oltz; Maxim N Artyomov Journal: Nat Aging Date: 2020-11-23
Authors: Ming-Tao Zhao; Haodong Chen; Qing Liu; Ning-Yi Shao; Nazish Sayed; Hung-Ta Wo; Joe Z Zhang; Sang-Ging Ong; Chun Liu; Youngkyun Kim; Huaxiao Yang; Tony Chour; Hong Ma; Nuria Marti Gutierrez; Ioannis Karakikes; Shoukhrat Mitalipov; Michael P Snyder; Joseph C Wu Journal: Proc Natl Acad Sci U S A Date: 2017-12-04 Impact factor: 11.205