RNA polymerase II at histone genes predicts outcome in human cancer

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

---

Real-time visualization of reconstituted transcription reveals RNA polymerase II activation mechanisms at single promoters

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

---

An RNA-centric view of transcription and genome organization

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

Published: Oct. 1, 2024

Language: Английский

---

Advances and applications in single-cell and spatial genomics

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

Published: Dec. 20, 2024

Language: Английский

---

Two distinct chromatin modules regulate proinflammatory gene expression

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

---

Shining a light on cell biology of the nucleus with single-cell sequencing

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

Published: Feb. 3, 2025

Language: Английский

---

Multimodal Insights into Adult Neurogenesis: An Integrative Review of Multi-Omics Approaches

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

Published: Feb. 1, 2025

Language: Английский

---

Anti-Phase Clustering of Regulatory Factors Shapes Gene Transcription Burst

Published: Jan. 1, 2025

Language: Английский

---

The spatial choreography of mRNA biosynthesis

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(4)

Published: Feb. 15, 2025

ABSTRACT Properly timed gene expression is essential for all aspects of organismal physiology. Despite significant progress, our understanding the complex mechanisms governing dynamics regulation in response to internal and external signals remains incomplete. Over past decade, advances technologies like light cryo-electron microscopy (Cryo-EM), tomography (Cryo-ET) high-throughput sequencing have spurred new insights into traditional paradigms expression. In this Review, we delve recent concepts addressing ‘where’ ‘when’ transcription RNA splicing occur within cells, emphasizing dynamic spatial temporal organization cell nucleus.

Language: Английский

---

PIS as a regulator of cellular heterogeneity, prognostic significance, and immune landscape in thyroid cancer

Translational Oncology, Journal Year: 2025, Volume and Issue: 55, P. 102296 - 102296

Published: March 25, 2025

Language: Английский

---