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

doi:10.1016/j.celrep.2019.05.046

Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis

Cell Rep. 2019 Jun 11;27(11):3228-3240.e7. doi: 10.1016/j.celrep.2019.05.046.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
⁵ 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.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Society of Fellows, Harvard University, Cambridge, MA 02138, USA.
⁷ Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA.
⁸ Laboratory of Membrane Biology, New York Blood Center, New York, NY 10065, USA; School of Life Science, Zhengzhou University, Zhengzhou, Henan 450001, China.
⁹ 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.
¹⁰ 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. Electronic address: aregev@broadinstitute.org.
¹¹ 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. Electronic address: sankaran@broadinstitute.org.

Abstract

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.

Keywords: GWAS; chromatin accessibility; erythropoiesis; hematopoiesis; human genetics; red blood cell; transcriptomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cells, Cultured
Chromatin / chemistry
Chromatin / metabolism
Chromatin Assembly and Disassembly*
Erythroid Precursor Cells / cytology
Erythroid Precursor Cells / metabolism
Erythropoiesis*
Female
GATA1 Transcription Factor / genetics
GATA1 Transcription Factor / metabolism
HEK293 Cells
Humans
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Middle Aged
Polymorphism, Single Nucleotide
Transcriptome*

Substances

Chromatin
GATA1 Transcription Factor
GATA1 protein, human
Kruppel-Like Transcription Factors
Membrane Proteins
TMCC2 protein, human
erythroid Kruppel-like factor

Abstract

Publication types

MeSH terms

Substances

Grants and funding