The pioneer factor OCT4 requires BRG1 to functionally mature gene regulatory elements in mouse embryonic stem cells
- University of Oxford, United Kingdom
Abstract
Pioneer transcription factors recognise and bind their target sequences in inaccessible chromatin to establish new transcriptional networks during development and cellular reprogramming. During this process, pioneer factors establish an accessible chromatin state to facilitate additional transcription factor binding, yet how different pioneer factors achieve this remains unclear. 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. BRG1 occupancy supports 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 shaping the activity of the pioneer factor OCT4 and regulating the pluripotency network.
Data availability
-
The pioneer factor OCT4 requires BRG1 to functionally mature gene regulatory elements in mouse embryonic stem cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE87822).
-
A comparative encyclopedia of DNA elements in the mouse genomePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE49847).
-
Enhancer Decommissioning by LSD1 During Embryonic Stem Cell DifferentiationPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE27844).
-
DNaseI Hypersensitivity by Digital DNaseI from ENCODE/University of WashingtonPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE37074).
-
INO80 complex in the core regulatory network governing ESC self-renewal [ChIP-Seq]Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE49137).
-
Genome-wide distribution and function of ATP-dependent chromatin remodelers in embryonic stem cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE64825).
-
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).
-
Expression data from OSKM-mediated 2nd reprogramming cells and the corresponding iPS cell linePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE67462).
-
The landscape of accessible chromatin in mammalian pre-implantation embryos (ATAC-Seq)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE66581).
-
Establishing Chromatin Regulatory Landscape during Mouse Preimplantation DevelopmentPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE76642).
Article and author information
Author details
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
© 2017, King & Klose
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.
Metrics
-
- 10,572
- views
-
- 1,594
- downloads
-
- 223
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The pioneer factor OCT4 requires BRG1 to functionally mature gene regulatory elements in mouse embryonic stem cells
eLife 6:e22631.
https://doi.org/10.7554/eLife.22631
Further reading
-
- Stem Cells and Regenerative Medicine
Cigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that NIC increases the abundance and proliferative activity of murine intestinal stem cells (ISCs) in vivo and ex vivo. Moreover, NIC induces Yes-associated protein (YAP) /Transcriptional coactivator with PDZ-binding motif (TAZ) and Notch signaling in ISCs via α7-nicotinic acetylcholine receptor (nAchR) and protein kinase C (PKC) activation; this effect was not detected in Paneth cells. The inhibition of Notch signaling by dibenzazepine (DBZ) nullified the effects of NIC on ISCs. NIC enhances in vivo tumor formation from ISCs after loss of the tumor suppressor gene Apc, DBZ inhibited NIC-induced tumor growth. Hence, this study identifies a NIC-triggered pathway regulating the stemness and tumorigenicity of ISCs and suggests the use of DBZ as a potential therapeutic strategy for treating intestinal tumors.
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.
