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Background: Sex differences in the transcriptome and epigenome are widespread in mouse liver and are associated with sex-bias in liver disease. Several thousand sex-differential distal enhancers have been identified; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization, DNA looping, and chromatin interactions are unknown.
Results: To address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were largely distal to sex-biased genes, but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors. A substantial subset of the sex-biased cohesin-non-CTCF binding sites, but not the sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer-promoter interactions are common. Sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. Furthermore, intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer-promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers.
Conclusions: These findings elucidate how 3-dimensional genome organization contributes to sex differences in gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.
Keywords
cohesin, CTCF, intra-TAD loops, 4C-seq, liver sex differences, Nipbl, DNase hypersensitive sites
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CURRENT STATUS: Published
View the published article at Epigenetics & Chromatin.
No community comments so far
Editorial decision: Accept
On 12 Jun, 2020
Editor assigned
On 23 May, 2020
Submission checks complete
On 22 May, 2020
Editor invited
On 22 May, 2020
No comments provided
Editorial decision: Minor revision
On 09 May, 2020
Review #1 received
Received 30 Apr, 2020
Reviewers invited
Invitations sent on 22 Apr, 2020
Reviewer #1 agreed
On 22 Apr, 2020
Editor assigned
On 18 Apr, 2020
Submission checks complete
On 17 Apr, 2020
Editor invited
On 17 Apr, 2020
Version 1
Posted 12 Feb, 2020
No comments provided
Editorial decision: Major revision
On 14 Mar, 2020
Review #2 received
Received 13 Mar, 2020
Review #1 received
Received 10 Mar, 2020
Reviewer #1 agreed
On 22 Feb, 2020
Reviewer #2 agreed
On 22 Feb, 2020
Reviewers invited
Invitations sent on 20 Feb, 2020
Editor assigned
On 12 Feb, 2020
Editor invited
On 11 Feb, 2020
Submission checks complete
On 11 Feb, 2020
First submitted
On 10 Feb, 2020
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Subject Areas
Epigenetics & Genomics
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See the published version of this preprint at Epigenetics & Chromatin.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
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Prescreen
This manuscript passed our Prescreen assessment
Complete author information
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Peer Review Timeline
CURRENT STATUS: Published
View the published article at Epigenetics & Chromatin.
No community comments so far
Editorial decision: Accept
On 12 Jun, 2020
Editor assigned
On 23 May, 2020
Submission checks complete
On 22 May, 2020
Editor invited
On 22 May, 2020
No comments provided
Editorial decision: Minor revision
On 09 May, 2020
Review #1 received
Received 30 Apr, 2020
Reviewers invited
Invitations sent on 22 Apr, 2020
Reviewer #1 agreed
On 22 Apr, 2020
Editor assigned
On 18 Apr, 2020
Submission checks complete
On 17 Apr, 2020
Editor invited
On 17 Apr, 2020
Version 1
Posted 12 Feb, 2020
No comments provided
Editorial decision: Major revision
On 14 Mar, 2020
Review #2 received
Received 13 Mar, 2020
Review #1 received
Received 10 Mar, 2020
Reviewer #1 agreed
On 22 Feb, 2020
Reviewer #2 agreed
On 22 Feb, 2020
Reviewers invited
Invitations sent on 20 Feb, 2020
Editor assigned
On 12 Feb, 2020
Editor invited
On 11 Feb, 2020
Submission checks complete
On 11 Feb, 2020
First submitted
On 10 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Epigenetics & Genomics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Epigenetics & Chromatin.
Background: Sex differences in the transcriptome and epigenome are widespread in mouse liver and are associated with sex-bias in liver disease. Several thousand sex-differential distal enhancers have been identified; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization, DNA looping, and chromatin interactions are unknown.
Results: To address these issues, we first characterized 1,847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were largely distal to sex-biased genes, but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors. A substantial subset of the sex-biased cohesin-non-CTCF binding sites, but not the sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer-promoter interactions are common. Sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. Furthermore, intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer-promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers.
Conclusions: These findings elucidate how 3-dimensional genome organization contributes to sex differences in gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
The full text of this article is available to read as a PDF.
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