Chromosome organization by one-sided and two-sided loop extrusion
- Massachusetts Institute of Technology, United States
- Harvard University, United States
- Northwestern University, United States
Abstract
SMC complexes, such as condensin or cohesin, organize chromatin throughout the cell cycle by a process known as loop extrusion. SMC complexes reel in DNA, extruding and progressively growing DNA loops. Modeling assuming two-sided loop extrusion reproduces key features of chromatin organization across different organisms. In vitro single-molecule experiments confirmed that yeast condensins extrude loops, however, they remain anchored to their loading sites and extrude loops in a 'one-sided' manner. We therefore simulate one-sided loop extrusion to investigate whether 'one-sided' complexes can compact mitotic chromosomes, organize interphase domains, and juxtapose bacterial chromosomal arms, as can be done by 'two-sided' loop extruders. While one-sided loop extrusion cannot reproduce these phenomena, variants can recapitulate in vivo observations. We predict that SMC complexes in vivo constitute effectively two-sided motors or exhibit biased loading and propose relevant experiments. Our work suggests that loop extrusion is a viable general mechanism of chromatin organization.
Data availability
Simulation and analysis code used to produce and analyze data has been made publicly available on GitHub. Methods and code documentation explains usage. In Figure 3, we show Hi-C data from another publication with GEO accession number GSE96107. In Figure 3 - figure supplement 8, we show Hi-C data from another publication with Bioproject accession number PRJNA427106. In Figure 4, we show Hi-C data from another publication with GEO accession number GSE68418.
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Multi-scale 3D genome rewiring during mouse neural developmentNCBI Gene Expression Omnibus, GSE96107.
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Condensin promotes the juxtaposition of DNA flanking its loading site in Bacillus subtilisNCBI Gene Expression Omnibus, GSE68418.
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Studies on chromosome structure at sub-nucleosome levelNCBI Bioproject, PRJNA427106.
Article and author information
Author details
Funding
National Institutes of Health (U54DK107980)
- Edward J Banigan
- Aafke A van den Berg
- Hugo B Brandão
- John F Marko
- Leonid A Mirny
National Institutes of Health (U54CA193419)
- Edward J Banigan
- Aafke A van den Berg
- Hugo B Brandão
- John F Marko
- Leonid A Mirny
National Institutes of Health (GM114190)
- Edward J Banigan
- Aafke A van den Berg
- Hugo B Brandão
- Leonid A Mirny
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Banigan 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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Chromosome organization by one-sided and two-sided loop extrusion
eLife 9:e53558.
https://doi.org/10.7554/eLife.53558
Further reading
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The environmental challenges the human malaria parasite, Plasmodium falciparum, faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light on the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using the CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate that PfMORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggests that PfMORC binds to not only sub-telomeric regions and genes involved in antigenic variation but may also play a role in modulating stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation of PfMORC impairs key histone marks and induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm that PfMORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies.
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During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme - the senescence associated secretory phenotype (SASP) - driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.
