Cohesin-dependence of neuronal gene expression relates to chromatin loop length
- Imperial College London, United Kingdom
- University of Bonn, Germany
- University of Pennsylvania, United States
- Rockefeller University, United States
Abstract
Cohesin and CTCF are major drivers of 3D genome organization, but their role in neurons is still emerging. Here we show a prominent role for cohesin in the expression of genes that facilitate neuronal maturation and homeostasis. Unexpectedly, we observed two major classes of activity-regulated genes with distinct reliance on cohesin in mouse primary cortical neurons. Immediate early genes remained fully inducible by KCl and BDNF, and short-range enhancer-promoter contacts at the Immediate early gene Fos formed robustly in the absence of cohesin. In contrast, cohesin was required for full expression of a subset of secondary response genes characterised by long-range chromatin contacts. Cohesin-dependence of constitutive neuronal genes with key functions in synaptic transmission and neurotransmitter signaling also scaled with chromatin loop length. Our data demonstrate that key genes required for the maturation and activation of primary cortical neurons depend on cohesin for their full expression, and that the degree to which these genes rely on cohesin scales with the genomic distance traversed by their chromatin contacts.
Data availability
RNAseq and 5C data generated in this study have been deposited at Gene Expression Omnibus under accession number GSE172429
-
Cohesin-dependence of neuronal gene expression relates to chromatin loop lengthNCBI Gene Expression Omnibus, GSE172429.
Article and author information
Author details
Matthias Merkenschlager
Funding
Medical Research Council
- Matthias Merkenschlager
Wellcome Trust (099276/Z/12/Z)
- Matthias Merkenschlager
European Molecular Biology Organization (ALTF 1047-2012)
- Lesly Calderon
Human Frontiers in Science Program (LT00427/2013)
- Lesly Calderon
National Institutes of Health (1R01-MH120269)
- Jennifer E Phillips-Cremins
National Institutes of Health (1DP1OD031253)
- Jennifer E Phillips-Cremins
National Institutes of Health (1R01-NS114226)
- Jennifer E Phillips-Cremins
4D Nucleome Common Fund (1U01DK127405)
- Jennifer E Phillips-Cremins
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jeremy J Day, University of Alabama at Birmingham, United States
Ethics
Animal experimentation: Laboratory bred mice of the appropriate genotype were maintained under SPF conditions and 12h light/dark cycle. Embryos were used to derive cells and tissues. Ethical approval was granted by the Home Office, UK, and the Imperial College London Animal Welfare and Ethical Review Body (AWERB).
Version history
- Preprint posted: February 24, 2021 (view preprint)
- Received: December 20, 2021
- Accepted: April 26, 2022
- Accepted Manuscript published: April 26, 2022 (version 1)
- Version of Record published: May 13, 2022 (version 2)
Copyright
© 2022, Calderon 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
-
- 3,834
- views
-
- 600
- downloads
-
- 46
- 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)
Cohesin-dependence of neuronal gene expression relates to chromatin loop length
eLife 11:e76539.
https://doi.org/10.7554/eLife.76539
Further reading
-
- Biochemistry and Chemical Biology
- Chromosomes and Gene Expression
Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrated that the human ortholog of Dhh1p, DDX6, triggers the deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.
-
- Chromosomes and Gene Expression
Tardigrades are microscopic animals renowned for their ability to withstand extreme conditions, including high doses of ionizing radiation (IR). To better understand their radio-resistance, we first characterized induction and repair of DNA double- and single-strand breaks after exposure to IR in the model species Hypsibius exemplaris. Importantly, we found that the rate of single-strand breaks induced was roughly equivalent to that in human cells, suggesting that DNA repair plays a predominant role in tardigrades’ radio-resistance. To identify novel tardigrade-specific genes involved, we next conducted a comparative transcriptomics analysis across three different species. In all three species, many DNA repair genes were among the most strongly overexpressed genes alongside a novel tardigrade-specific gene, which we named Tardigrade DNA damage Response 1 (TDR1). We found that TDR1 protein interacts with DNA and forms aggregates at high concentration suggesting it may condensate DNA and preserve chromosome organization until DNA repair is accomplished. Remarkably, when expressed in human cells, TDR1 improved resistance to Bleomycin, a radiomimetic drug. Based on these findings, we propose that TDR1 is a novel tardigrade-specific gene conferring resistance to IR. Our study sheds light on mechanisms of DNA repair helping cope with high levels of DNA damage inflicted by IR.
