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Immunity. 2018 Feb 20;48(2):227-242.e8. doi: 10.1016/j.immuni.2018.01.013.

Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells.

Author information

1
Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address: hug21@nhlbi.nih.gov.
2
Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
3
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
4
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
5
Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
6
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
7
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: evroth@its.caltech.edu.
8
Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address: zhaok@nhlbi.nih.gov.

Abstract

How chromatin reorganization coordinates differentiation and lineage commitment from hematopoietic stem and progenitor cells (HSPCs) to mature immune cells has not been well understood. Here, we carried out an integrative analysis of chromatin accessibility, topologically associating domains, AB compartments, and gene expression from HSPCs to CD4+CD8+ T cells. We found that abrupt genome-wide changes at all three levels of chromatin organization occur during the transition from double-negative stage 2 (DN2) to DN3, accompanying the T lineage commitment. The transcription factor BCL11B, a critical regulator of T cell commitment, is associated with increased chromatin interaction, and Bcl11b deletion compromised chromatin interaction at its target genes. We propose that these large-scale and concerted changes in chromatin organization present an energy barrier to prevent the cell from reversing its fate to earlier stages or redirecting to alternatives and thus lock the cell fate into the T lineages.

KEYWORDS:

4D nucleome; AB compartment conversion; AD connectivity; BCL11B; DNase hypersensitive sites; T cell development; chromatin conformation; lineage commitment

PMID:
29466755
PMCID:
PMC5847274
DOI:
10.1016/j.immuni.2018.01.013
[Indexed for MEDLINE]
Free PMC Article

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