High-throughput Oligopaint screen identifies druggable 3D genome regulators

Nature, Год журнала: 2023, Номер 620(7972), С. 209 - 217

Опубликована: Июль 12, 2023

Язык: Английский

---

Full circle: a brief history of cohesin and the regulation of gene expression

FEBS Journal, Год журнала: 2022, Номер 290(7), С. 1670 - 1687

Опубликована: Янв. 20, 2022

The cohesin complex has a range of crucial functions in the cell. Cohesin is essential for mediating chromatid cohesion during mitosis, repair double‐strand DNA breaks, and control gene transcription. This last function been subject intense research ever since discovery cohesin's role long‐range regulation cut Drosophila. Subsequent showed that expression some genes exquisitely sensitive to depletion, while others remain relatively unperturbed. Sensitivity depletion also remarkably cell type‐ and/or condition‐specific. recent integral forming chromatin loops via loop extrusion should explain much regulatory properties, but surprisingly, failed identify ‘one size fits all’ mechanism how controls expression. review will illustrate early examples cohesin‐dependent integrate with later work on genome organization mechanisms by which regulates

Язык: Английский

---

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(13), С. 6788 - 6788

Опубликована: Июнь 24, 2021

The cohesin complex is crucial for mediating sister chromatid cohesion and hierarchal three-dimensional organization of the genome. Mutations in genes are present a range cancers. Extensive research over last few years has shown that mutations key events contribute to neoplastic transformation. Cohesin involved cellular processes; therefore, impact cancer can be cell context dependent. Candidate targets with therapeutic potential mutant cells emerging from functional studies. Here, we review pharmacological agents have cells.

Язык: Английский

---

Clinical and biological aspects of myeloid leukemia in Down syndrome

Leukemia, Год журнала: 2021, Номер 35(12), С. 3352 - 3360

Опубликована: Сен. 13, 2021

Язык: Английский

---

STAG2 mutations regulate 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(6), С. 107341 - 107341

Опубликована: Май 3, 2024

Inactivating mutations of genes encoding the cohesin complex are common in a wide range human cancers. STAG2 is most commonly mutated subunit. Here we report impact stable correction endogenous, naturally occurring on gene expression, 3D genome organization, chromatin loops, and Polycomb signaling glioblastoma multiforme (GBM). In two GBM cell lines, their significantly altered expression ∼10% all expressed genes. Virtually highly regulated were negatively by (i.e., higher STAG2-mutant cells), one them—HEPH—was uncultured tumors as well. While had little effect large-scale features organization (A/B compartments, TADs), did alter thousands individual some which controlled adjacent Loops specific to cells, STAG1-containing complexes, very large, supporting prior findings that complexes have greater loop extrusion processivity than STAG2-containing suggesting long loops may be general feature Finally, mutation activated activity leading increased H3K27me3 marks, identifying potential target for therapeutic intervention tumors. Together, these illuminate landscape STAG2-regulated genes, A/B pathways GBM, providing important clues into largely still unknown mechanism tumor suppression.

Язык: Английский

---

STAG2 Regulates Homologous Recombination Repair and Sensitivity to ATM Inhibition

Advanced Science, Год журнала: 2023, Номер 10(36)

Опубликована: Ноя. 20, 2023

Stromal antigen 2 (STAG2), a subunit of the cohesin complex, is recurrently mutated in various tumors. However, role STAG2 DNA repair and its therapeutic implications are largely unknown. Here it reported that knockout results increased double-stranded breaks (DSBs) chromosomal aberrations by reducing homologous recombination (HR) repair, confers hypersensitivity to inhibitors ataxia telangiectasia (ATMi), Poly ADP Ribose Polymerase (PARPi), or combination both. Of note, impaired HR STAG2-deficiency mainly attributed restored expression KMT5A, which turn methylates H4K20 (H4K20me0) H4K20me1 thereby decreases recruitment BRCA1-BARD1 chromatin. Importantly, correlates with poor prognosis cancer patients. identified as an important regulator potential strategy for STAG2-mutant tumors elucidated.

Язык: Английский

---

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

Frontiers in Molecular Biosciences, Год журнала: 2021, Номер 8

Опубликована: Июль 27, 2021

Cornelia de Lange Syndrome (CdLS) is a human developmental syndrome with complex multisystem phenotypic features. It has been traditionally considered cohesinopathy together other phenotypically related diseases because of their association mutations in subunits the cohesin complex. Despite some overlap, clinical manifestations cohesinopathies vary considerably and, although precise molecular mechanisms are not well defined yet, potential pathomechanisms underlying these diverse defects have theoretically linked to alterations function. The plays critical role sister chromatid cohesion, but this function affected CdLS. In last decades, non-cohesion-related on transcriptional regulation established and CdLS pathoetiology recently associated gene expression deregulation. Up 70% cases cohesin-loading factor NIPBL , which shown play prominent chromatin architecture regulation. Therefore, it suggested that can be transcriptomopathy. Actually, CdLS-like phenotypes chromatin-associated proteins, as KMT2A, AFF4, EP300, TAF6, SETD5, SMARCB1, MAU2, ZMYND11, MED13L, PHIP, ARID1B, NAA10, BRD4 or ANKRD11, most no known direct cohesin. case BRD4, highly investigated coregulator, an interaction revealed, providing evidence cooperation developmentally important genes. This new finding reinforces notion altered program during development major etiological basis for review, we intend integrate recent available CdLS, highlighting data favors transcription-centered framework, support idea could conceptualized

Язык: Английский

---

Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts

Cells, Год журнала: 2024, Номер 13(7), С. 608 - 608

Опубликована: Март 30, 2024

Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and stability maintenance. Genomic analyses have detected mutations the cohesin wide array of human tumors. These findings led to increased interest as potential target cancer therapy. Synthetic lethality has been suggested an approach exploit genetic differences cells influence their selective killing. In this study, we show that ESCO1, NIPBL, PDS5B, RAD21, SMC1A, SMC3, STAG2, WAPL genes are synthetically lethal with stimulation WNT signaling obtained following LY2090314 treatment, GSK3 inhibitor, several cell lines. Moreover, treatment stabilization β-catenin affected c-MYC, probably due occupancy decrease at c-MYC promoter. Finally, caused dysregulation mainly involving pathways related transcription proliferation, chromatin remodeling. For first time, our work provides underlying molecular basis for synthetic suggests targeting may be promising therapeutic tumors carrying mutated cohesin.

Язык: Английский

---

Prevalence of and gene regulatory constraints on transcriptional adaptation in single cells

Genome biology, Год журнала: 2024, Номер 25(1)

Опубликована: Авг. 12, 2024

Cells and tissues have a remarkable ability to adapt genetic perturbations via variety of molecular mechanisms. Nonsense-induced transcriptional compensation, form adaptation, has recently emerged as one such mechanism, in which nonsense mutations gene trigger upregulation related genes, possibly conferring robustness at cellular organismal levels. However, beyond handful developmental contexts curated sets no comprehensive genome-wide investigation this behavior been undertaken for mammalian cell types conditions. How the regulatory-level effects inherently stochastic compensatory networks contribute phenotypic penetrance single cells remains unclear. We analyze existing bulk single-cell transcriptomic datasets uncover prevalence adaptation systems across diverse types. perform regulon expression analyses transcription factor target both pooled perturbation datasets. Our results reveal greater regulons factors exhibiting compared those that do not. Stochastic mathematical modeling minimal qualitatively recapitulates several aspects including paralog mutation. Combined with machine learning analysis network features interest, our framework offers potential explanations regulatory steps are most important adaptation. integrative approach identifies putative hits—genes demonstrating possible adaptation—to follow-up on experimentally provides formal quantitative test refine models

Язык: Английский

---

Rules of Program Behavior

ACM Transactions on Computing Education, Год журнала: 2021, Номер 21(4), С. 1 - 37

Опубликована: Ноя. 17, 2021

We propose a framework for identifying, organizing, and communicating learning objectives that involve program semantics. In this framework, detailed are written down as rules of behavior (RPBs). RPBs teacher-facing statements describe what needs to be learned about the specific sort programs. Different programming languages, student cohorts, contexts call different RPBs. Instructional designers may define progressions RPB rulesets stages course or curriculum; we identify evaluation criteria discuss tradeoffs in design. As proof-of-concept example, present progression designed teaching beginners how expressions, variables, functions work Python. submit is valuable practitioners researchers tool design communication. Within computing education research, can inform, among other things, ongoing exploration “notional machines” assessments visualizations. The theoretical report here lays foundation future empirical research compares effectiveness well methods particular ruleset.

Язык: Английский

---