Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer DOI Creative Commons
Dig Bijay Mahat, Heena Kumra,

Sarah A Castro

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It characterized by activating KRAS mutations and p53 alterations. However, how these dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of tumor microenvironment (TME) remains poorly understood. Here, we show that

Language: Английский

RNA polymerase II at histone genes predicts outcome in human cancer DOI
Steven Henikoff, Ye Zheng, Ronald M. Paranal

et al.

Science, Journal Year: 2025, Volume and Issue: 387(6735), P. 737 - 743

Published: Jan. 2, 2025

Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)–cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide FFPE sections. We demonstrate global RNAPII elevations mouse gliomas assorted tumors small clinical samples discover regional corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. occupancy at S-phase-dependent histone genes correlated with WHO grade meningiomas, accurately predicted rapid recurrence, corresponded whole-arm chromosome losses. Elevated meningiomas diverse breast cancers consistent production being rate-limiting S-phase progression gene driving overproliferation aneuploidy general implications precision oncology.

Language: Английский

Citations

4
Real-time visualization of reconstituted transcription reveals RNA polymerase II activation mechanisms at single promoters DOI Creative Commons
Megan Palacio, Dylan J. Taatjes

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

RNA polymerase II (RNAPII) is regulated by sequence-specific transcription factors (TFs) and the pre-initiation complex (PIC): TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, Mediator. TFs Mediator contain intrinsically-disordered regions (IDRs) form phase-separated condensates, but how IDRs control RNAPII function remains poorly understood. Using purified PIC factors, we developed a Real-time In-vitro Fluorescence Transcription assay (RIFT) for second-by-second visualization of at hundreds promoters simultaneously. We show rapid activation IDR-dependent, without condensate formation. For example, MED1-IDR can functionally replace native TF, activating with similar (not identical) kinetics; however, squelches as condensate, activates single-protein. cooperatively activate bursting re-initiation surprisingly, drive TF-promoter recruitment, TF-DNA binding. Collectively, RIFT addressed questions largely intractable cell-based methods, yielding mechanistic insights about IDRs, enhancer-promoter communication, that complement live-cell imaging data.

Language: Английский

Citations

2
An RNA-centric view of transcription and genome organization DOI
Jonathan E. Henninger, Richard A. Young

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(19), P. 3627 - 3643

Published: Oct. 1, 2024

Language: Английский

Citations

8
Advances and applications in single-cell and spatial genomics DOI
Jingjing Wang, Fang Ye, Haoxi Chai

et al.

Science China Life Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Language: Английский

Citations

7
Two distinct chromatin modules regulate proinflammatory gene expression DOI Creative Commons
Isabelle Seufert, Irene Gerosa, Vassiliki Varamogianni‐Mamatsi

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 6, 2024

Abstract Various mechanisms have been proposed to explain gene activation and co-regulation, including enhancer-promoter interactions via chromatin looping the enrichment of transcription factors into hubs or condensates. However, these conclusions often stem from analyses individual loci, genome-wide studies exploring mechanistic differences with coupled expression are lacking. In this study, we dissected proinflammatory program induced by TNFα in primary human endothelial cells using NGS- imaging-based techniques. Our findings, enabled our novel RWireX approach for single-cell ATAC-seq analysis, revealed two distinct regulatory modules: autonomous links co-accessibility (ACs) between separated sites, domains contiguous (DCs) increased local factor binding. Genes ACs DCs exhibited different transcriptional bursting kinetics, highlighting existence structurally functionally modules response. These findings provide a framework understanding how achieve rapid precise control. Graphical abstract Highlights Two distinct, non-mutually exclusive modules, DCs, that regulate were identified based on deep scATAC-seq. represent long-range genomic regulation occurring more burst frequency. regions binding can modulate size. The AC/DC model integrates sequencing-based evidence microscopy observations hubs/condensates unified model.

Language: Английский

Citations

4
Single-cell RNA-sequencing and genome-wide Mendelian randomisation along with abundant machine learning methods identify a novel B cells signature in gastric cancer DOI Creative Commons

Qi Ma,

Jie Gao, Yuan Hui

et al.

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 6, 2025

Gastric cancer (GC) has a poor prognosis, considerable cellular heterogeneity, and ranks fifth among malignant tumours. Understanding the tumour microenvironment (TME) intra-tumor heterogeneity (ITH) may lead to development of novel GC treatments. The single-cell RNA sequencing (scRNA-seq) dataset was obtained from Gene Expression Omnibus (GEO) database, where diverse immune cells were isolated re-annotated based on cell markers established in original study ascertain their individual characteristics. We conducted weighted gene co-expression network analysis (WGCNA) identify genes with significant correlation GC. Utilising bulk data, we employed machine learning integration methods train specific biomarkers for diagnostic combinations. A two-sample Mendelian randomisation performed investigate causal effect gastric (GC). Ultimately, utilised DSigDB database acquire associations between signature pharmaceuticals. 18 that made up as follows: ZFAND2A, PBX4, RAMP2, NNMT, RNASE1, CD93, CDH5, NFKBIE, VWF, DAB2, FAAH2, VAT1, MRAS, TSPAN4, EPAS1, AFAP1L1, DNM3. Patients categorised into high-risk low-risk groups according risk scores. Individuals cohort exhibited dismal outlook. demonstrated individuals genetic predisposition elevated NFKBIE levels heightened likelihood acquiring Molecular docking indicates gemcitabine chloropyramine serve effective therapeutics against NFKBIE. developed validated utilising scRNA-seq data patients. function biomarker therapeutic target

Language: Английский

Citations

0
Chromatin-centric insights into DNA replication DOI
Yang Liu, Zhengrong Zhangding, Xuhao Liu

et al.

Trends in Genetics, Journal Year: 2025, Volume and Issue: 41(5), P. 412 - 424

Published: Jan. 7, 2025

Language: Английский

Citations

0
Shining a light on cell biology of the nucleus with single-cell sequencing DOI Creative Commons
Jeroen van den Berg, Peter Zeller

Current Opinion in Cell Biology, Journal Year: 2025, Volume and Issue: 93, P. 102468 - 102468

Published: Feb. 3, 2025

Language: Английский

Citations

0
Multimodal Insights into Adult Neurogenesis: An Integrative Review of Multi-Omics Approaches DOI Creative Commons
Jin Li, Leyi Huang, Wenjie Xiao

et al.

Heliyon, Journal Year: 2025, Volume and Issue: 11(4), P. e42668 - e42668

Published: Feb. 1, 2025

Language: Английский

Citations

0
Anti-Phase Clustering of Regulatory Factors Shapes Gene Transcription Burst DOI
Bitong Li, Yew Yan Wong, Neftali Flores‐Rodriguez

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0