Local chromatin fiber folding represses transcription and loop extrusion in quiescent cells
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Evaluation Summary:
This work characterizes chromatin compaction in quiescent yeast cells and its role in the repression of gene expression. The authors' findings that chromatin compaction via heterogeneous interactions between nucleosomes directly contributes to transcriptional repression provides a useful conceptual paradigm for studies of quiescence in other organisms.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
A longstanding hypothesis is that chromatin fiber folding mediated by interactions between nearby nucleosomes represses transcription. However, it has been difficult to determine the relationship between local chromatin fiber compaction and transcription in cells. Further, global changes in fiber diameters have not been observed, even between interphase and mitotic chromosomes. We show that an increase in the range of local inter-nucleosomal contacts in quiescent yeast drives the compaction of chromatin fibers genome-wide. Unlike actively dividing cells, inter-nucleosomal interactions in quiescent cells require a basic patch in the histone H4 tail. This quiescence-specific fiber folding globally represses transcription and inhibits chromatin loop extrusion by condensin. These results reveal that global changes in chromatin fiber compaction can occur during cell state transitions, and establish physiological roles for local chromatin fiber folding in regulating transcription and chromatin domain formation.
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Evaluation Summary:
This work characterizes chromatin compaction in quiescent yeast cells and its role in the repression of gene expression. The authors' findings that chromatin compaction via heterogeneous interactions between nucleosomes directly contributes to transcriptional repression provides a useful conceptual paradigm for studies of quiescence in other organisms.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The manuscript by Swygert et al. characterizes the local chromatin compaction (less than 1 KB) in quiescent yeast cells and its role in the repression of gene expression. The authors conclude that Q cells have increased heterogeneous interactions between nucleosomes beyond N+1, resulting in a disordered 10-30 nm fiber. These interactions require the basic patch of histone H4 and are blocked by H4 acetylation. Q induced local compaction occurs independent of condensin and represses transcription at a subset of genes that partially overlap genes repressed by condensin. These conclusions are supported by well-executed and generally well-performed experiments. These insights into the changes in chromatin structure and their impact on transcription silencing in quiescent cells will provide a useful conceptual and …
Reviewer #1 (Public Review):
The manuscript by Swygert et al. characterizes the local chromatin compaction (less than 1 KB) in quiescent yeast cells and its role in the repression of gene expression. The authors conclude that Q cells have increased heterogeneous interactions between nucleosomes beyond N+1, resulting in a disordered 10-30 nm fiber. These interactions require the basic patch of histone H4 and are blocked by H4 acetylation. Q induced local compaction occurs independent of condensin and represses transcription at a subset of genes that partially overlap genes repressed by condensin. These conclusions are supported by well-executed and generally well-performed experiments. These insights into the changes in chromatin structure and their impact on transcription silencing in quiescent cells will provide a useful conceptual and technical paradigm for studies of quiescence in other organisms.
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Reviewer #2 (Public Review):
In their paper, 'Local chromatin fiber folding represses transcription and loop extrusion in quiescent cells,' Swygert et al combine high-resolution Hi-C analyses with a slew of imaging, chemical perturbation, and computational experiments to investigate how chromatin folding in quiescent S. cerevisiae cells. This is an impressive paper - the authors perform multiple orthogonal analyses to demonstrate that quiescent yeast nuclei do, indeed, harbor a distinct chromatin structure compared to log-phase yeast nuclei, one in which the chromatin fiber is (on average) folded into a more compact structure during quiescence. The authors then employ a mixture of chemical and genetic perturbations to provide compelling evidence that 1.) this folded fiber structure represses transcription (though fiber folding is not …
Reviewer #2 (Public Review):
In their paper, 'Local chromatin fiber folding represses transcription and loop extrusion in quiescent cells,' Swygert et al combine high-resolution Hi-C analyses with a slew of imaging, chemical perturbation, and computational experiments to investigate how chromatin folding in quiescent S. cerevisiae cells. This is an impressive paper - the authors perform multiple orthogonal analyses to demonstrate that quiescent yeast nuclei do, indeed, harbor a distinct chromatin structure compared to log-phase yeast nuclei, one in which the chromatin fiber is (on average) folded into a more compact structure during quiescence. The authors then employ a mixture of chemical and genetic perturbations to provide compelling evidence that 1.) this folded fiber structure represses transcription (though fiber folding is not absolutely necessary for transcriptional repression), and 2.) that a basic patch in the tail of core histone H4 is necessary for maintaining fiber folding in quiescence, in part through interactions with a lysine deacetylase. While these findings are likely to be of interest to the chromatin field at large, this paper does have some weaknesses relating to data interpretation and experimental interpretation that should be addressed by the authors.
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