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

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 1, 2023

Abstract 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 than STAG2-corrected 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 STAG2-containing suggesting long loops may be general feature Finally, STAG2-regulated enriched for H3K27me3 epigenetic mark, revealing inactivation can activate GBM, identifying potential target therapeutic intervention tumors. Together, these illuminate landscape genes, A/B pathways providing important clues into largely still unknown mechanism tumor suppression.

Language: Английский

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Computational Analysis of Cohesin Complex Genes and their Role in the Pathogenesis of AML

Clinical and Experimental Health Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 7, 2024

Objective: Anomalies in the cohesion complex contribute to pathogenesis of myeloid malignancies by affecting self-renewal capacity hematopoietic and progenitor stem cells, but underlying mechanisms this phenotype are not fully understood. Therefore, study aims shed light on relationship between AML comprehensively determining mutations expression profiles genes constituting investigating effect survival using bioinformatics databases tools. Methods: A total 96 different were identified 13 genes. Out these mutations, 26 classified as pathogenic/oncogenic. The levels STAG1, REC8, MAU2, CDCA5, PDS5B significantly higher patient group compared healthy (p< .01). Survival analysis based low high gene revealed that increased REC8 was associated with (p= .024), which is considered a prognostic marker. In STRING analysis, it determined hub proteins interact acetyltransferases ESCO1 ESCO2 involved sister chromatid cohesion, TERF1, component telomere nucleoprotein complex, PDS5A BRCA2, functionally related genetic stability recombination, respectively. Results: An increase language outcomes, particularly repetition, observed following treatments. It also found therapy gains more robust bihemispheric stimulation posterior temporal sites inferior frontal targets. Conclusion: Overall, none target except mutated showed significant independent clinical outcome defined overall survival. However, we have diversity alterations individual cohesin subunits through comprehensive molecular analysis. results may be beneficial development targeted drug therapies personalized medicine approaches.

Language: Английский

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Genetic variation as a long-distance modulator of RAD21 expression in humans

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: July 29, 2022

Abstract Somatic mutations and changes in expression of RAD21 are common many types cancer. Moreover, sub-optimal levels early development can result cohesinopathies. Altered directly from the gene. However, whether DNA variants outside gene could control its thereby contribute to cancer developmental disease is unknown. In this study, we searched for genomic that modify determine their potential or by dysregulation. We 42,953,834 a spatial-eQTL association with transcription RAD21. identified 123 significant associations (FDR < 0.05), which local ( cis ) long-distance trans regulators expression. The co-regulate further seven genes AARD , AKAP11 GRID1 KCNIP4 RCN1 TRIOBP USP32 ), enriched having Sp2 factor binding sites promoter regions. six had previously been associated onset, progression, metastasis. Our results suggest genome-wide variation non-coding regions impacts on transcript addition other genes, then impact oncogenesis process ubiquitination. This identification distant co-regulation oncogenes represents strategy discovery novel genetic influencing onset diagnostics.

Language: Английский

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The three-dimensional genome in zebrafish development

Briefings in Functional Genomics, Journal Year: 2021, Volume and Issue: unknown

Published: Feb. 3, 2021

In recent years, remarkable progress has been made toward understanding the three-dimensional (3D) organisation of genomes and influence genome on gene regulation. Although 3D probably plays a crucial role in embryo development, animal studies addressing developmental roles chromosome topology are only just starting to emerge. Zebrafish, an important model system for early have already contributed advances consequences perturbation organisation. Zebrafish used determine effects mutations proteins responsible organisation: cohesin CTCF. this review, we highlight research date from zebrafish that provided insight into how contributes tissue-specific regulation development.

Language: Английский

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Discovery of Latent Drivers from Double Mutations in Pan-Cancer Data Reveal their Clinical Impact

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: April 4, 2021

Abstract Background Transforming patient-specific molecular data into clinical decisions is fundamental to personalized medicine. Despite massive advancements in cancer genomics, date driver mutations whose frequencies are low, and their observable transformation potential minor have escaped identification. Yet, when paired with other cis , such ‘latent driver’ can drive cancer. Here, we discover double mutations. Method We applied a statistical approach identify significantly co-occurring the pan-cancer of mutation profiles ∼80,000 tumor sequences from TCGA AACR GENIE databases. The components same gene doublets were assessed as latent drivers. merged analysis significant drug response cell lines patient derived xenografts (PDXs). This allowed us link impact information signatures for some types. Results Our comprehensive identified 228 which 113 cataloged Oncogenic activation protein be through either single or multiple independent mechanisms action. Combinations driver, weak strong leading fully activated state high rate. Tumor suppressors require higher mutational load coincide compared oncogenes implies relative robustness losing functions. Evaluation patient-derived xenograft treatment indicate that certain genes increase oncogenic activity, hence better (e.g. PIK3CA), they promote resistance drugs EGFR). Conclusion allele genome landscapes emphasizes interrogation big genomic integration results large-scale small-molecule sensitivity provide deep patterns rare; but still result dramatic phenotypic alterations,

Language: Английский

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