The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells

Abstract
Data availability
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Abstract

Pioneer transcription factors recognise and bind their target sequences in inaccessible chromatin to establish new transcriptional networks throughout development and cellular reprogramming. During this process, pioneer factors establish an accessible chromatin state to facilitate additional transcription factor binding, yet it remains unclear how different pioneer factors achieve this. Here, we discover that the pluripotency-associated pioneer factor OCT4 binds chromatin to shape accessibility, transcription factor co-binding, and regulatory element function in mouse embryonic stem cells. Chromatin accessibility at OCT4-bound sites requires the chromatin remodeller BRG1, which is recruited to these sites by OCT4 to support additional transcription factor binding and expression of the pluripotency-associated transcriptome. Furthermore, the requirement for BRG1 in shaping OCT4 binding reflects how these target sites are used during cellular reprogramming and early mouse development. Together this reveals a distinct requirement for a chromatin remodeller in promoting the activity of the pioneer factor OCT4 and regulating the pluripotency network.

Data availability

The following data sets were generated

1. King HW
2. Klose RJ
(2017) The pioneer factor OCT4 requires BRG1 to functionally mature gene regulatory elements in mouse embryonic stem cells
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE87822).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE87822

The following previously published data sets were used

1. ENCODE DCC
(2014) A comparative encyclopedia of DNA elements in the mouse genome
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE49847).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE49847
1. Young RA
(2012) Enhancer Decommissioning by LSD1 During Embryonic Stem Cell Differentiation
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE27844).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE27844
1. Sandstrom R
(2012) DNaseI Hypersensitivity by Digital DNaseI from ENCODE/University of Washington
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE37074).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=gse37074
1. Wang L
2. Hu G
3. Du Y
(2014) INO80 complex in the core regulatory network governing ESC self-renewal [ChIP-Seq]
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE49137).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE49137
1. Hmitou I
2. de Dieuleveult M
3. Depaux A
4. Chantalat S
5. Yen K
6. Pugh BF
7. Gérard M
(2016) Genome-wide distribution and function of ATP-dependent chromatin remodelers in embryonic stem cells
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE64825).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64825
1. Xing Y
2. Carstens R
(2016) Multiphasic and dynamic changes in alternative splicing during induction of pluripotency are coordinated by numerous RNA binding proteins [iPS]
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE70022).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70022
1. Li M
(2015) Expression data from OSKM-mediated 2nd reprogramming cells and the corresponding iPS cell line
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE67462).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=gse67462
1. Wu J
2. Huang B
3. Chen H
4. Xie W
(2016) The landscape of accessible chromatin in mammalian pre-implantation embryos (ATAC-Seq)
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE66581).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66581
1. Lu F
2. Liu Y
3. Inoue A
4. Suzuki T
5. Zhao K
6. Zhang Y
(2016) Establishing Chromatin Regulatory Landscape during Mouse Preimplantation Development
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE76642).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE76642

Article and author information

Author details

Hamish W King

Department of Biochemistry, University of Oxford, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5972-8926
Robert J Klose

Department of Biochemistry, University of Oxford, Oxford, United Kingdom

For correspondence
rob.klose@bioch.ox.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8726-7888

Funding

Wellcome (098024/Z/11/Z)

Robert J Klose

European Research Council (681440)

Robert J Klose

Exeter College, University of Oxford (Monsanto Senior Research Fellowship)

Robert J Klose

Lister Institute of Preventive Medicine

Robert J Klose

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

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.