Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis

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

Cell Reports (Jun 2019)

Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis

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

Affiliations

Leif S. Ludwig: Division 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
Caleb A. Lareau: Division 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, USA
Erik L. Bao: Division 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, USA
Satish K. Nandakumar: Division 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
Christoph Muus: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
Jacob C. Ulirsch: Division 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, USA
Kaitavjeet Chowdhary: Division 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, USA
Jason D. Buenrostro: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Society of Fellows, Harvard University, Cambridge, MA 02138, USA
Narla Mohandas: Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA
Xiuli An: Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA; School of Life Science, Zhengzhou University, Zhengzhou, Henan 450001, China
Martin J. Aryee: Broad 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, USA
Aviv Regev: Broad 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 author
Vijay G. Sankaran: Division 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 author

Journal volume & issue: Vol. 27, no. 11
pp. 3228 – 3240.e7

Abstract

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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

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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