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Nat Immunol. 2018 Sep;19(9):932-941. doi: 10.1038/s41590-018-0184-1. Epub 2018 Aug 20.

Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation.

Author information

1
Lymphocyte Development Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
2
MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
3
Computational Regulatory Genomics Group, Integrative Biology Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
4
Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
5
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
6
Department of Surgery and Cancer, Department of Medicine, Imperial College London, London, UK.
7
Hospital Sírio-Libanês, Sao Paulo, Brazil.
8
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
9
Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
10
BioFrontiers Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.
11
Department of Biochemistry, University of Oxford, Oxford, UK.
12
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna Biocenter, Vienna, Austria.
13
Humanitas Clinical and Research Center, Milan, Italy.
14
Humanitas University, Milan, Italy.
15
Lymphocyte Development Group, Epigenetics Section, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK. matthias.merkenschlager@lms.mrc.ac.uk.

Abstract

Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.

PMID:
30127433
PMCID:
PMC6195188
[Available on 2019-02-20]
DOI:
10.1038/s41590-018-0184-1

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