Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis

Summary: Human erythropoiesis serves as a paradigm of physiologic cellular differentiation. This process is also of considerable interest for better understanding anemias and identifying new therapies. Here, we apply deep transcriptomic and accessible chromatin profiling to characterize a faithful e...

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Main Authors:	Leif S. Ludwig, Caleb A. Lareau, Erik L. Bao, Satish K. Nandakumar, Christoph Muus, Jacob C. Ulirsch, Kaitavjeet Chowdhary, Jason D. Buenrostro, Narla Mohandas, Xiuli An, Martin J. Aryee, Aviv Regev, Vijay G. Sankaran
Format:	Article
Language:	English
Published:	Elsevier 2019-06-01
Series:	Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211124719306667

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record_format	Article
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Leif S. Ludwig Caleb A. Lareau Erik L. Bao Satish K. Nandakumar Christoph Muus Jacob C. Ulirsch Kaitavjeet Chowdhary Jason D. Buenrostro Narla Mohandas Xiuli An Martin J. Aryee Aviv Regev Vijay G. Sankaran
spellingShingle	Leif S. Ludwig Caleb A. Lareau Erik L. Bao Satish K. Nandakumar Christoph Muus Jacob C. Ulirsch Kaitavjeet Chowdhary Jason D. Buenrostro Narla Mohandas Xiuli An Martin J. Aryee Aviv Regev Vijay G. Sankaran Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis Cell Reports
author_facet	Leif S. Ludwig Caleb A. Lareau Erik L. Bao Satish K. Nandakumar Christoph Muus Jacob C. Ulirsch Kaitavjeet Chowdhary Jason D. Buenrostro Narla Mohandas Xiuli An Martin J. Aryee Aviv Regev Vijay G. Sankaran
author_sort	Leif S. Ludwig
title	Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis
title_short	Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis
title_full	Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis
title_fullStr	Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis
title_full_unstemmed	Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis
title_sort	transcriptional states and chromatin accessibility underlying human erythropoiesis
publisher	Elsevier
series	Cell Reports
issn	2211-1247
publishDate	2019-06-01
description	Summary: Human erythropoiesis serves as a paradigm of physiologic cellular differentiation. This process is also of considerable interest for better understanding anemias and identifying new therapies. Here, we apply deep transcriptomic and accessible chromatin profiling to characterize a faithful ex vivo human erythroid differentiation system from hematopoietic stem and progenitor cells. We reveal stage-specific transcriptional states and chromatin accessibility during various stages of erythropoiesis, including 14,260 differentially expressed genes and 63,659 variably accessible chromatin peaks. Our analysis suggests differentiation stage-predominant roles for specific master regulators, including GATA1 and KLF1. We integrate chromatin profiles with common and rare genetic variants associated with erythroid cell traits and diseases, finding that variants regulating different erythroid phenotypes likely act at variable points during differentiation. In addition, we identify a regulator of terminal erythropoiesis, TMCC2, more broadly illustrating the value of this comprehensive analysis to improve our understanding of erythropoiesis in health and disease. : Ludwig et al. chart the dynamic transcriptional and chromatin landscapes as hematopoietic stem and progenitor cells differentiate into mature red blood cells. This multi-omic profiling reveals dynamic transcription factor activities and human genetic variation that modulate this process. Keywords: erythropoiesis, red blood cell, chromatin accessibility, transcriptomics, GWAS, human genetics, hematopoiesis
url	http://www.sciencedirect.com/science/article/pii/S2211124719306667
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spelling	doaj-6398f2df4d4c4128b606c247249494a42020-11-24T22:15:13ZengElsevierCell Reports2211-12472019-06-01271132283240.e7Transcriptional States and Chromatin Accessibility Underlying Human ErythropoiesisLeif S. Ludwig0Caleb A. Lareau1Erik L. Bao2Satish K. Nandakumar3Christoph Muus4Jacob C. Ulirsch5Kaitavjeet Chowdhary6Jason D. Buenrostro7Narla Mohandas8Xiuli An9Martin J. Aryee10Aviv Regev11Vijay G. Sankaran12Division of Hematology/Oncology, Boston Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USADivision of Hematology/Oncology, Boston Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USADivision of Hematology/Oncology, Boston Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USADivision of Hematology/Oncology, Boston Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USADivision of Hematology/Oncology, Boston Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USADivision of Hematology/Oncology, Boston Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Society of Fellows, Harvard University, Cambridge, MA 02138, USALaboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USALaboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA; School of Life Science, Zhengzhou University, Zhengzhou, Henan 450001, ChinaBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USABroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 26309, USA; Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Corresponding authorDivision of Hematology/Oncology, Boston Children’s Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding authorSummary: Human erythropoiesis serves as a paradigm of physiologic cellular differentiation. This process is also of considerable interest for better understanding anemias and identifying new therapies. Here, we apply deep transcriptomic and accessible chromatin profiling to characterize a faithful ex vivo human erythroid differentiation system from hematopoietic stem and progenitor cells. We reveal stage-specific transcriptional states and chromatin accessibility during various stages of erythropoiesis, including 14,260 differentially expressed genes and 63,659 variably accessible chromatin peaks. Our analysis suggests differentiation stage-predominant roles for specific master regulators, including GATA1 and KLF1. We integrate chromatin profiles with common and rare genetic variants associated with erythroid cell traits and diseases, finding that variants regulating different erythroid phenotypes likely act at variable points during differentiation. In addition, we identify a regulator of terminal erythropoiesis, TMCC2, more broadly illustrating the value of this comprehensive analysis to improve our understanding of erythropoiesis in health and disease. : Ludwig et al. chart the dynamic transcriptional and chromatin landscapes as hematopoietic stem and progenitor cells differentiate into mature red blood cells. This multi-omic profiling reveals dynamic transcription factor activities and human genetic variation that modulate this process. Keywords: erythropoiesis, red blood cell, chromatin accessibility, transcriptomics, GWAS, human genetics, hematopoiesishttp://www.sciencedirect.com/science/article/pii/S2211124719306667

Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis

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