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
-
- 10,590
- views
-
- 1,596
- 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
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.
-
- Stem Cells and Regenerative Medicine
Tissue necrosis is a devastating complication for many human diseases and injuries. Unfortunately, our understanding of necrosis and how it impacts surrounding healthy tissue – an essential consideration when developing effective methods to treat such injuries – has been limited by a lack of robust genetically tractable models. Our lab previously established a method to study necrosis-induced regeneration in the Drosophila wing imaginal disc, which revealed a unique phenomenon whereby cells at a distance from the injury upregulate caspase activity in a process called Necrosis-induced Apoptosis (NiA) that is vital for regeneration. Here, we have further investigated this phenomenon, showing that NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge. Furthermore, we find that a proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration. This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism. These data reveal a new means by which non-apoptotic Dronc signaling promotes regenerative proliferation in response to necrotic damage.
