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Kenneth Mills
Queen's University Belfast
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6362-4481
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Background The cohesin complex plays a major role in folding the human genome into 3D structural domains. Mutations in members of the cohesin complex are known early drivers of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with STAG2 the most frequently mutated complex member.
Methods Here we use functional genomics (RNA-seq, ChIP-seq and HiChiIP) to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming in a clinically relevant model of chronic STAG2 loss.
Results The chronic loss of STAG2 led to loss of smaller loop domains and the maintenance/formation of large domains that in turn led to altered genome compartmentalisation. These changes in genome structure lead to altered gene expression, including deregulation of the HOXA locus and the MAPK signalling pathway resulting in increased sensitivity to MEK inhibition.
Conclusions The altered genomic architecture driven by the chronic loss of STAG2 results in altered gene expression that may contribute to leukaemogenesis which may be therapeutically targeted.
Keywords
STAG2, cohesin, acute myeloid leukaemia, RNA-seq, ChIP-seq, HIChIP, HOX, MAPK pathway
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Peer Review Timeline
CURRENT STATUS: Published
View the published article at Journal of Translational Medicine.
No community comments so far
Editorial decision: Accept
On 14 Aug, 2020
Editor assigned
On 13 Aug, 2020
Submission checks complete
On 12 Aug, 2020
Editor invited
On 12 Aug, 2020
Version 1
Posted 02 Jun, 2020
No comments provided
Editorial decision: Major revision
On 22 Jun, 2020
Review #1 received
Received 20 Jun, 2020
Review #2 received
Received 20 Jun, 2020
Reviewer #2 agreed
On 08 Jun, 2020
Reviewer #1 agreed
On 06 Jun, 2020
Reviewers invited
Invitations sent on 05 Jun, 2020
Editor assigned
On 05 Jun, 2020
Editor invited
On 04 Jun, 2020
Submission checks complete
On 29 May, 2020
First submitted
On 26 May, 2020
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See the published version of this preprint at Journal of Translational Medicine.
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
Kenneth Mills
Queen's University Belfast
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6362-4481
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Journal of Translational Medicine.
No community comments so far
Editorial decision: Accept
On 14 Aug, 2020
Editor assigned
On 13 Aug, 2020
Submission checks complete
On 12 Aug, 2020
Editor invited
On 12 Aug, 2020
Version 1
Posted 02 Jun, 2020
No comments provided
Editorial decision: Major revision
On 22 Jun, 2020
Review #1 received
Received 20 Jun, 2020
Review #2 received
Received 20 Jun, 2020
Reviewer #2 agreed
On 08 Jun, 2020
Reviewer #1 agreed
On 06 Jun, 2020
Reviewers invited
Invitations sent on 05 Jun, 2020
Editor assigned
On 05 Jun, 2020
Editor invited
On 04 Jun, 2020
Submission checks complete
On 29 May, 2020
First submitted
On 26 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Journal of Translational Medicine.
Background The cohesin complex plays a major role in folding the human genome into 3D structural domains. Mutations in members of the cohesin complex are known early drivers of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with STAG2 the most frequently mutated complex member.
Methods Here we use functional genomics (RNA-seq, ChIP-seq and HiChiIP) to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming in a clinically relevant model of chronic STAG2 loss.
Results The chronic loss of STAG2 led to loss of smaller loop domains and the maintenance/formation of large domains that in turn led to altered genome compartmentalisation. These changes in genome structure lead to altered gene expression, including deregulation of the HOXA locus and the MAPK signalling pathway resulting in increased sensitivity to MEK inhibition.
Conclusions The altered genomic architecture driven by the chronic loss of STAG2 results in altered gene expression that may contribute to leukaemogenesis which may be therapeutically targeted.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
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