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).
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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Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
