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.
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On 03 Sep, 2020
On 14 Aug, 2020
On 13 Aug, 2020
On 12 Aug, 2020
On 12 Aug, 2020
Posted 02 Jun, 2020
On 22 Jun, 2020
Received 20 Jun, 2020
Received 20 Jun, 2020
On 08 Jun, 2020
On 06 Jun, 2020
Invitations sent on 05 Jun, 2020
On 05 Jun, 2020
On 04 Jun, 2020
On 29 May, 2020
On 26 May, 2020
On 03 Sep, 2020
On 14 Aug, 2020
On 13 Aug, 2020
On 12 Aug, 2020
On 12 Aug, 2020
Posted 02 Jun, 2020
On 22 Jun, 2020
Received 20 Jun, 2020
Received 20 Jun, 2020
On 08 Jun, 2020
On 06 Jun, 2020
Invitations sent on 05 Jun, 2020
On 05 Jun, 2020
On 04 Jun, 2020
On 29 May, 2020
On 26 May, 2020
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
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