Transcription factors TCF-1 and GATA3 are key factors for the epigenetic priming of early innate lymphoid progenitors toward distinct cell fates

Gang Ren; Binbin Lai; Christelle Harly; Songjoon Baek; Yi Ding; Mingzhu Zheng; Yaqiang Cao; Kairong Cui; Yu Yang; Jinfang Zhu; Gordon L Hager; Avinash Bhandoola; Keji Zhao

doi:10.1016/j.immuni.2022.06.019

Transcription factors TCF-1 and GATA3 are key factors for the epigenetic priming of early innate lymphoid progenitors toward distinct cell fates

Immunity. 2022 Aug 9;55(8):1402-1413.e4. doi: 10.1016/j.immuni.2022.06.019. Epub 2022 Jul 25.

Authors

Gang Ren¹, Binbin Lai², Christelle Harly³, Songjoon Baek⁴, Yi Ding³, Mingzhu Zheng⁵, Yaqiang Cao⁶, Kairong Cui⁶, Yu Yang⁷, Jinfang Zhu⁸, Gordon L Hager⁴, Avinash Bhandoola³, Keji Zhao⁹

Affiliations

¹ Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA; Northwest Agriculture and Forest University, College of Animal Science and Technology, Yangling, Shaanxi 712100, China.
² Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA; Biomedical Engineering Department, Peking University, Beijing 100191, China; Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China.
³ Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Department of Microbiology and Immunology, School of Medicine, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
⁶ Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
⁷ Biomedical Engineering Department, Peking University, Beijing 100191, China; Department of Dermatology and Venereology, Peking University First Hospital, Beijing 100034, China.
⁸ Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁹ Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address: zhaok@nhlbi.nih.gov.

Abstract

The differentiation of innate lymphoid cells (ILCs) from hematopoietic stem cells needs to go through several multipotent progenitor stages. However, it remains unclear whether the fates of multipotent progenitors are predefined by epigenetic states. Here, we report the identification of distinct accessible chromatin regions in all lymphoid progenitors (ALPs), EILPs, and ILC precursors (ILCPs). Single-cell MNase-seq analyses revealed that EILPs contained distinct subpopulations epigenetically primed toward either dendritic cell lineages or ILC lineages. We found that TCF-1 and GATA3 co-bound to the lineage-defining sites for ILCs (LDS-Is), whereas PU.1 binding was enriched in the LDSs for alternative dendritic cells (LDS-As). TCF-1 and GATA3 were indispensable for the epigenetic priming of LDSs at the EILP stage. Our results suggest that the multipotency of progenitor cells is defined by the existence of a heterogeneous population of cells epigenetically primed for distinct downstream lineages, which are regulated by key transcription factors.

Keywords: ChIC-seq; EILPs; GATA3; ILCPs; PU.1; TCF-1; epigenetic priming; multipotency; scMNase-seq; single-cell epigenomics.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Cell Differentiation
Cell Lineage
Epigenesis, Genetic
Hematopoietic Stem Cells
Immunity, Innate*
Lymphocytes*

Abstract

Publication types

MeSH terms

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