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DeSUMOylation limits the rapid transcriptional reprogramming induced by anthracyclines in Acute Myeloid Leukemias

ABSTRACT: Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR) but not the nucleoside analog Cytarabine, the two main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 hours) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, accelerating deSUMOylation dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Although DNR does not modify CTCF binding on chromatin in general and at NFKB2 promoter in particular, it leads to a SUMO-dependent reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with distal cis-regulatory regions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231023 | GEO | 2023/06/23

REPOSITORIES: GEO

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SUMOylation controls the rapid transcriptional reprogramming induced by chemotherapies in Acute Myeloid Leukemias

Project description:Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces broad transcriptional changes in AML cells before cell death induction. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, which limits both the positive and negative effects of DNR on transcription. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Its induction is preceded by a SUMO-dependent reconfiguration of chromatin loops engaging its CTCF- and SUMO-bound promoter with distal cis-regulatory regions. Altogether, our work suggests that one of the earliest effects of DNR in AML cells is a SUMO-dependent transcriptional reprogramming.

2023-06-23 | PXD032956 | Pride

SUMOylation regulates daunorubicin-induced changes in the long-range interactions between NFKB2 promoter and distant genomic regions in HL-60 cells

Project description:SUMOylation, a post-translational modification of the ubiquitin family plays key roles in Acute Myeloid Leukemias response to therapies, in particular through the regulation of gene expression. We have found that the NFKB2 gene is rapidly induced by DNR in the HL-60 cell line and inhibition of SUMOylation limits is induction. To decipher how SUMOylation controls DNR-induced NFKB2 expression, we analyzed the dynamic of the 3D conformation of the NFKB2 gene using Circularized Chromosome Conformation Capture (4C). We found that the NFKB2 promoter interacts with four distal regions. DNR induced a loss of one of the interaction and the gain of a new interaction. Inhibition of SUMOylation with ML-792 did not affect the interactions between NFKB2 promoter and distal genomic regions. However, inhibition of SUMOylation prevented DNR-regulated changes in the 3D architecture of the locus.

2023-06-23 | GSE198981 | GEO

Acute depletion of CTCF rewires genome-wide chromatin accessibility

Project description:The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription. Here we systematically integrated multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, CRISPR-Cas9 survival dropout screening, time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewired genome-wide chromatin accessibility. Increased accessible chromatin regions were largely located adjacent to CTCF-binding sites at promoter regions and insulator sites and were associated with enhanced transcription of nearby genes. In addition, we used CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners in regulating downstream gene expression. We successfully identified 40 candidates, including multiple established partners (i.e., MYC) supported by all layers of evidence. Interestingly, many CTCF co-regulators (e.g., YY1, ZBTB7A) that have evident alterations of respective downstream gene expression do not show changes at their expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription. This study highlights CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation

2021-07-04 | PXD026484 | Pride

SUMO2/3 CHIP-Seq in HL-60 cells treated or not with cytarabine or daunorubicine

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2023-06-23 | GSE198985 | GEO

SUMO-2/3 ChIP-Seq in HL-60 cells treated or not with Daunorubicin, Cytarabin and the Nox inhibitor VAS2870

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2023-12-30 | E-MTAB-4947 | biostudies-arrayexpress

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2021-04-13 | PXD018049 | Pride

TORC1 shapes the SUMO proteome to control RNA polymerase III activity

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2017-01-01 | GSE85622 | GEO

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2019-11-01 | PXD013884 | Pride

Chromatin-Associated SUMOylation Controls the Transcriptional Switch between Plant Development and Heat Stress Responses

Project description:The post-translational protein modiﬁcation known as SUMOylation has conserved roles in the heat stress responses of various species. The functional connection between the global regulation of gene expression and chromatin-associated SUMOylation in plant cells isunknown. Here, we uncovereda genome-wide relationship between chromatin-associated SUMOylation and transcriptional switches in Arabidopsis thaliana grown at room temperature, exposed to heat stress, and exposed to heat stress followed by recovery. The small ubiquitin-like modiﬁer (SUMO)-associated chromatin sites, characterized by whole-genome ChIP-seq, were generally associated with active chromatin markers. In response to heat stress, chromatin-associated SUMO signals increased at promoter-transcriptional start site regions and decreased in gene bodies. RNAseqanalysissupportedthe role ofchromatin-associatedSUMOylationin transcriptionalactivation duringrapid responses to high temperature. Changes inSUMO signals on chromatinwere associated with the upregulation ofheat-responsivegenesandthedownregulationofgrowth-relatedgenes.DisruptionoftheSUMOligasegene SIZ1 abolished SUMO signals on chromatin and attenuated rapid transcriptional responses to heat stress. The SUMO signal peaks were enriched in DNA elements recognized by distinct groups of transcription factors under different temperature conditions. These observations provide evidence that chromatin-associated SUMOylation regulates the transcriptional switch between development and heat stress response in plant cells.

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2019-10-07 | PXD013346 | Pride

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