CTCF confers local nucleosome resiliency after DNA replication and during mitosis
- Institut Pasteur, France
- University of California, San Francisco, United States
Abstract
The access of Transcription Factors (TFs) to their cognate DNA binding motifs requires a precise control over nucleosome positioning. This is especially important following DNA replication and during mitosis, both resulting in profound changes in nucleosome organization over TF binding regions. Using mouse Embryonic Stem (ES) cells, we show that the TF CTCF displaces nucleosomes from its binding site and locally organizes large and phased nucleosomal arrays, not only in interphase steady-state but also immediately after replication and during mitosis. Correlative analyses suggest this is associated with fast gene reactivation following replication and mitosis. While regions bound by other TFs (Oct4/Sox2), display major rearrangement, the post-replication and mitotic nucleosome positioning activity of CTCF is not unique: Esrrb binding regions are also characterized by persistent nucleosome positioning. Therefore, selected TFs such as CTCF and Esrrb act as resilient TFs governing the inheritance of nucleosome positioning at regulatory regions throughout the cell-cycle.
Data availability
Sequencing data generated for this study have been deposited in GEO with accession GSE131356.Publicly available datasets used here: Festuccia et al. 2019; GEO accession: GSE122589; Teves et al. 2018; GEO accession: GSE109963; Stewart-Morgan et al. 2019; GEO accession: GSE128643
-
CTCF confers local nucleosome resiliency after DNA replication and during mitosisNCBI Gene Expression Omnibus, GSE131356.
-
Role of TBP in reactivation of transcription following mitosis [RNA-Seq]NCBI Gene Expression Omnibus, GSE109963.
-
Transcription factor activity and nucleosome organisation in mitosisNCBI Gene Expression Omnibus, GSE122589.
-
Transcription Restart Establishes Chromatin Accessibility after DNA ReplicationNCBI Gene Expression Omnibus, GSE128643.
Article and author information
Author details
Michel Cohen-Tannoudji
Funding
Institut Pasteur
- Michel Cohen-Tannoudji
- Pablo Navarro
Centre National de la Recherche Scientifique
- Michel Cohen-Tannoudji
- Pablo Navarro
Agence Nationale de la Recherche (Investissement d'Avenir; Revive Labex; ANR-10-LABX-73)
- Pablo Navarro
Agence Nationale de la Recherche (ANR 16 CE12 0004 01 MITMAT)
- Pablo Navarro
Ligue Contre le Cancer (LNCC EL2018 NAVARRO)
- Pablo Navarro
European Research Council (ERC-CoG-2017 BIND)
- Pablo Navarro
European Molecular Biology Organization (ALTF523-2013)
- Elphège P Nora
Human Frontier Science Program
- Elphège P Nora
Fondation Schlumberger (FRM FSER 2017)
- Pablo Navarro
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted according to the French and European regulations on care and protection of laboratory animals (EC Directive 86/609, French Law 2001-486 issued on June 6, 2001) and were approved by the Institut Pasteur ethics committee (n{degree sign} dha180008).
Copyright
© 2019, Owens et al.
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
-
- 5,506
- views
-
- 742
- downloads
-
- 70
- 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)
CTCF confers local nucleosome resiliency after DNA replication and during mitosis
eLife 8:e47898.
https://doi.org/10.7554/eLife.47898
Further reading
-
- Cell Biology
- Chromosomes and Gene Expression
Meiotic crossover recombination is essential for both accurate chromosome segregation and the generation of new haplotypes for natural selection to act upon. This requirement is known as crossover assurance and is one example of crossover control. While the conserved role of the ATPase, PCH-2, during meiotic prophase has been enigmatic, a universal phenotype when pch-2 or its orthologs are mutated is a change in the number and distribution of meiotic crossovers. Here, we show that PCH-2 controls the number and distribution of crossovers by antagonizing their formation. This antagonism produces different effects at different stages of meiotic prophase: early in meiotic prophase, PCH-2 prevents double-strand breaks from becoming crossover-eligible intermediates, limiting crossover formation at sites of initial double-strand break formation and homolog interactions. Later in meiotic prophase, PCH-2 winnows the number of crossover-eligible intermediates, contributing to the designation of crossovers and ultimately, crossover assurance. We also demonstrate that PCH-2 accomplishes this regulation through the meiotic HORMAD, HIM-3. Our data strongly support a model in which PCH-2’s conserved role is to remodel meiotic HORMADs throughout meiotic prophase to destabilize crossover-eligible precursors and coordinate meiotic recombination with synapsis, ensuring the progressive implementation of meiotic recombination and explaining its function in the pachytene checkpoint and crossover control.
-
- Cancer Biology
- Chromosomes and Gene Expression
Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1’s phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.
