Cohesin mutations are synthetic lethal with stimulation of WNT signaling DOI Creative Commons

Chue Vin Chin,

Jisha Antony, Sarada Ketharnathan

и другие.

eLife, Год журнала: 2020, Номер 9

Опубликована: Дек. 7, 2020

Mutations in genes encoding subunits of the cohesin complex are common several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations SMC3, RAD21, and STAG2 screened for synthetic lethality 3009 FDA-approved compounds. The screen identified compounds that interfere transcription, DNA damage repair cycle. Unexpectedly, one top ‘hits’ was a GSK3 inhibitor, an agonist Wnt signaling. show sensitivity to inhibition is likely due stabilization β-catenin cohesin-mutant cells, Wnt-responsive gene expression highly sensitized -mutant CMK leukemia cells. Moreover, activity enhanced zebrafish mutant stag2b rad21 . Our results suggest could progress oncogenesis by enhancing signaling, targeting pathway represent novel therapeutic strategy cancers.

Язык: Английский

Brain and cancer associated binding domain mutations provide insight into CTCF’s relationship with chromatin and its contribution to gene regulation DOI Open Access
Catherine Do,

Guimei Jiang,

Giulia Cova

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 12, 2024

Here we used a series of CTCF mutations to explore CTCF's relationship with chromatin and its contribution gene regulation. impact depends on the genomic context bound sites unique binding properties WT mutant proteins. Specifically, signal strength is linked changes in accessibility, ability block cohesin stability. Multivariate modelling reveals that both accessibility contribute independently insulation, however has stronger effect. have bidirectional such at sites, reduced cohesin-dependent, specific fashion. In addition, each alters TF an indirect manner, which impart most influence rewiring transcriptional networks cell's differentiate. Collectively, perturbations provide rich resource for determining site-specific effects.

Язык: Английский

Процитировано

5
How DNA loop extrusion mediated by cohesin enables V(D)J recombination DOI Creative Commons
Jan‐Michael Peters

Current Opinion in Cell Biology, Год журнала: 2021, Номер 70, С. 75 - 83

Опубликована: Янв. 9, 2021

'Structural maintenance of chromosomes' (SMC) complexes are required for the folding genomic DNA into loops. Theoretical considerations and single-molecule experiments performed with SMC cohesin condensin indicate that occurs via loop extrusion. Recent work indicates this process is essential assembly antigen receptor genes by V(D)J recombination in developing B T cells vertebrate immune system. Here, I review how recent studies mouse immunoglobulin heavy chain locus Igh have provided evidence hypothesis formation chromatin loops regulation CTCF Wapl might ensure all variable gene segments (VH segments) participate a re-arranged DJH segment, to generation maximally diverse repertoire B-cell receptors antibodies.

Язык: Английский

Процитировано

32
Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors DOI Creative Commons
Ryuichiro Nakato,

Toyonori Sakata,

Jiankang Wang

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Сен. 19, 2023

Abstract Cohesin regulates gene expression through context-specific chromatin folding mechanisms such as enhancer–promoter looping and topologically associating domain (TAD) formation by cooperating with factors cohesin loaders the insulation factor CTCF. We developed a computational workflow to explore how three-dimensional (3D) structure are regulated collectively or individually related factors. The main component is CustardPy, which multi-omics datasets compared systematically. To validate our methodology, we generated 3D genome, transcriptome, epigenome data before after depletion of effects depletion. observed diverse on genome changes were correlated splitting TADs caused loss. also variations in long-range interactions across TADs, their epigenomic states. These tools will be valuable for studies.

Язык: Английский

Процитировано

13
LoopSage: An energy-based Monte Carlo approach for the loop extrusion modeling of chromatin DOI
Sevastianos Korsak, Dariusz Plewczyński

Methods, Год журнала: 2024, Номер 223, С. 106 - 117

Опубликована: Янв. 29, 2024

Язык: Английский

Процитировано

5
Cohesin mutations are synthetic lethal with stimulation of WNT signaling DOI Creative Commons

Chue Vin Chin,

Jisha Antony, Sarada Ketharnathan

и другие.

eLife, Год журнала: 2020, Номер 9

Опубликована: Дек. 7, 2020

Mutations in genes encoding subunits of the cohesin complex are common several cancers, but may also expose druggable vulnerabilities. We generated isogenic MCF10A cell lines with deletion mutations SMC3, RAD21, and STAG2 screened for synthetic lethality 3009 FDA-approved compounds. The screen identified compounds that interfere transcription, DNA damage repair cycle. Unexpectedly, one top ‘hits’ was a GSK3 inhibitor, an agonist Wnt signaling. show sensitivity to inhibition is likely due stabilization β-catenin cohesin-mutant cells, Wnt-responsive gene expression highly sensitized -mutant CMK leukemia cells. Moreover, activity enhanced zebrafish mutant stag2b rad21 . Our results suggest could progress oncogenesis by enhancing signaling, targeting pathway represent novel therapeutic strategy cancers.

Язык: Английский

Процитировано

31