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
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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.
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).
Reviewing Editor
- Jeremy J Day, University of Alabama at Birmingham, United States
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.
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Cohesin-dependence of neuronal gene expression relates to chromatin loop length
eLife 11:e76539.
https://doi.org/10.7554/eLife.76539
Further reading
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- Cell Biology
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The cohesin complex plays essential roles in chromosome segregation, 3D genome organisation, and DNA damage repair through its ability to modify DNA topology. In higher eukaryotes, meiotic chromosome function, and therefore fertility, requires cohesin complexes containing meiosis-specific kleisin subunits: REC8 and RAD21L in mammals and REC-8 and COH-3/4 in Caenorhabditis elegans. How these complexes perform the multiple functions of cohesin during meiosis and whether this involves different modes of DNA binding or dynamic association with chromosomes is poorly understood. Combining time-resolved methods of protein removal with live imaging and exploiting the temporospatial organisation of the C. elegans germline, we show that REC-8 complexes provide sister chromatid cohesion (SCC) and DNA repair, while COH-3/4 complexes control higher-order chromosome structure. High-abundance COH-3/4 complexes associate dynamically with individual chromatids in a manner dependent on cohesin loading (SCC-2) and removal (WAPL-1) factors. In contrast, low-abundance REC-8 complexes associate stably with chromosomes, tethering sister chromatids from S-phase until the meiotic divisions. Our results reveal that kleisin identity determines the function of meiotic cohesin by controlling the mode and regulation of cohesin–DNA association, and are consistent with a model in which SCC and DNA looping are performed by variant cohesin complexes that coexist on chromosomes.
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- Chromosomes and Gene Expression
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Though long non-coding RNAs (lncRNAs) represent a substantial fraction of the Pol II transcripts in multicellular animals, only a few have known functions. Here we report that the blocking activity of the Bithorax complex (BX-C) Fub-1 boundary is segmentally regulated by its own lncRNA. The Fub-1 boundary is located between the Ultrabithorax (Ubx) gene and the bxd/pbx regulatory domain, which is responsible for regulating Ubx expression in parasegment PS6/segment A1. Fub-1 consists of two hypersensitive sites, HS1 and HS2. HS1 is an insulator while HS2 functions primarily as an lncRNA promoter. To activate Ubx expression in PS6/A1, enhancers in the bxd/pbx domain must be able to bypass Fub-1 blocking activity. We show that the expression of the Fub-1 lncRNAs in PS6/A1 from the HS2 promoter inactivates Fub-1 insulating activity. Inactivation is due to read-through as the HS2 promoter must be directed toward HS1 to disrupt blocking.
