Tumor suppressor SMARCB1 suppresses super-enhancers to govern hESC lineage determination

Abstract
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Abstract

The SWI/SNF complex is a critical regulator of pluripotency in human embryonic stem cells (hESCs), and individual subunits have varied and specific roles during development and in diseases. The core subunit SMARCB1 is required for early embryonic survival, and mutations can give rise to atypical teratoid/rhabdoid tumors (AT/RTs) in the pediatric central nervous system. We report that in contrast to other studied systems, SMARCB1 represses bivalent genes in hESCs and antagonizes chromatin accessibility at super-enhancers. Moreover, and consistent with its established role as a CNS tumor suppressor, we find that SMARCB1 is essential for neural induction but dispensable for mesodermal or endodermal differentiation. Mechanistically, we demonstrate that SMARCB1 is essential for hESC super-enhancer silencing in neural differentiation conditions. This genomic assessment of hESC chromatin regulation by SMARCB1 reveals a novel positive regulatory function at super-enhancers and a unique lineage-specific role in regulating hESC differentiation.

Data availability

All raw RNAseq and ATACseq data have been made available in NCBI's Gene Expression Omnibus (Edgar, 2002), with accession number GSE128351.

The following data sets were generated

(2019) Tumor suppressor SMARCB1 suppresses super-enhancers to govern hESC 2 lineage determination
NCBI Gene Expression Omnibus, GSE128351.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE128351

Article and author information

Author details

Lee F Langer

Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, United States

Competing interests
The authors declare that no competing interests exist.
James M Ward

Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Trevor K Archer

Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, United States

For correspondence
archer1@niehs.nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7651-3644

Funding

National Institute of Environmental Health Sciences (Z01 ES071006-18)

Trevor K Archer

National Institute of General Medical Sciences (GM120018)

Lee F Langer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.