Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence DOI
Simon Linder, Marlous Hoogstraat, Suzan Stelloo

et al.

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(9), P. 2074 - 2097

Published: June 27, 2022

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk cancer enrolled a neoadjuvant clinical trial. Transcriptomic demonstrated that inhibition drove tumors toward neuroendocrine-like state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming pioneer factor FOXA1 inactive chromatin sites active cis-regulatory elements dictate prosurvival signals. Notably, treatment-induced were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels associated patients' outcomes, knockout strongly decreased cell growth. Our data highlight remarkable cistromic plasticity following AR-targeted an acquired dependency regulator ARNTL, novel candidate therapeutic target.Understanding cancers interventions critical identifying drug targets improve management treatment-resistant disease. study signaling uncovered as vulnerability inhibition, presenting lead development. See related commentary by Zhang et al., p. 2017. This article highlighted Issue feature, 2007.

Language: Английский

An atlas of cells in the human tonsil DOI Creative Commons
Ramon Massoni-Badosa, Sergio Aguilar-Fernández, Juan C. Nieto

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(2), P. 379 - 399.e18

Published: Jan. 31, 2024

Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas human tonsil composed >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well spatial transcriptomics. This census identified 121 cell types states, defined developmental trajectories, enabled understanding functional units tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer locally active in follicle-associated T B cells, SIX5 putative transcriptional regulator plasma maturation. Analyses validation cohort confirmed presence, annotation, markers tonsillar provided evidence age-related compositional shifts. demonstrate value this resource by annotating from cell-derived mantle lymphomas, linking heterogeneity to normal differentiation states

Language: Английский

Citations

48
TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation DOI Creative Commons
Andrea Pichler, Nadège Carrié,

Marine Cuisinier

et al.

Immunity, Journal Year: 2023, Volume and Issue: 56(7), P. 1631 - 1648.e10

Published: June 30, 2023

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by and its role in immune surveillance remain unresolved. Using T cell-specific deletion agonist antibodies, we found that modulates tumor infiltration of CD8+-exhausted (Tex) cells expressing PD1, Lag-3, Tim-3 inhibitory receptors. cell-intrinsic, TCR-independent signaling stimulated proliferation terminal differentiation Tex precursor through mechanism involving RelA cRel canonical NF-κB subunits Tox-dependent chromatin remodeling. While cell accumulation induced prophylactic agonists favored growth, anti-PD1 efficacy was improved with subsequent stimulation pre-clinical mouse models. Better understanding exhaustion has crucial implications for treatment infectious diseases. Our results identify as critical regulator expansion holds potential broad therapeutic applications.

Language: Английский

Citations

42
Near telomere-to-telomere genome of the model plant Physcomitrium patens DOI
Guiqi Bi,

Shijun Zhao,

Jiawei Yao

et al.

Nature Plants, Journal Year: 2024, Volume and Issue: 10(2), P. 327 - 343

Published: Jan. 26, 2024

Language: Английский

Citations

36
The sirtuin-associated human senescence program converges on the activation of placenta-specific gene PAPPA DOI

Shijia Bi,

Xiaoyu Jiang, Qianzhao Ji

et al.

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(8), P. 991 - 1009.e12

Published: March 13, 2024

Language: Английский

Citations

17
An activity-specificity trade-off encoded in human transcription factors DOI Creative Commons

Julian Naderi,

Alexandre P. Magalhães,

Gözde Kibar

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(8), P. 1309 - 1321

Published: July 5, 2024

Abstract Transcription factors (TFs) control specificity and activity of gene transcription, but whether a relationship between these two features exists is unclear. Here we provide evidence for an evolutionary trade-off the in human TFs encoded as submaximal dispersion aromatic residues their intrinsically disordered protein regions. We identified approximately 500 that encode short periodic blocks regions, resembling imperfect prion-like sequences. Mutation reduced transcriptional activity, whereas increasing multiple enhanced reprogramming efficiency, promoted liquid–liquid phase separation vitro more promiscuous DNA binding cells. Together with recent work on enhancer elements, results suggest important role suboptimal control. propose rational engineering amino acid alter may be strategy to optimize TF-dependent processes, including cellular reprogramming.

Language: Английский

Citations

16
Pan-phylum genomes of hornworts reveal conserved autosomes but dynamic accessory and sex chromosomes DOI
Peter Schafran,

Duncan A. Hauser,

Jessica Nelson

et al.

Nature Plants, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Language: Английский

Citations

3
Removal of toxic steroidal glycoalkaloids and bitterness in tomato is controlled by a complex epigenetic and genetic network DOI Creative Commons

Feng Bai,

Mengbo Wu, Wei Huang

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(8)

Published: Feb. 19, 2025

The steroidal glycoalkaloids (SGAs) produced in Solanaceae crops, including tomato, are antinutritional because of their cellular toxicity and resultant bitter taste to humans. To make fruits palatable, SGA profiles shift from toxic α-tomatine nonbitter nontoxic esculeoside A during the ripening process. However, mechanisms regulating this conversion remain unclear. In study, we showed that removal SGAs is under control DNA demethylation, ethylene, key transcription factors by forming a feedback loop governs expression GLYCOALKALOID METABOLISM ( GAME ) genes ripening. Moreover, ethylene-inducible NON-RIPENING, RIPENING INHIBITOR, FRUITFULL1 coordinately regulate GAME31 , GAME40 GAME5 glycoalkaloid transporter gene GORKY whereas jasmonic acid–induced MYC2 modulates GAME36 . Furthermore, demethylation mediated DEMETER - LIKE 2 drives detoxification tomato domestication.

Language: Английский

Citations

3
Wound-inducible WUSCHEL-RELATED HOMEOBOX 13 is required for callus growth and organ reconnection DOI Creative Commons
Momoko Ikeuchi, Akira Iwase, Tasuku Ito

et al.

PLANT PHYSIOLOGY, Journal Year: 2021, Volume and Issue: 188(1), P. 425 - 441

Published: Nov. 2, 2021

Abstract Highly efficient tissue repair is pivotal for surviving damage-associated stress. Plants generate callus upon injury to heal wound sites, yet regulatory mechanisms of remain elusive. Here, we identified WUSCHEL-RELATED HOMEOBOX 13 (WOX13) as a key regulator formation and organ adhesion in Arabidopsis (Arabidopsis thaliana). WOX13 belongs an ancient subclade the WOX family, previous study shows that orthologs moss Physcomitrium patens (PpWOX13L) are involved cellular reprogramming at sites. We found wox13 mutant totally defective establishing reconnection grafting, suggesting crucial seed plants. expression rapidly induced wounding, which was partly dependent on activity AP2/ERF transcription factor, WOUND-INDUCED DEDIFFERENTIATION 1 (WIND1). turn directly upregulated WIND2 WIND3 further promote regeneration. also orchestrates transcriptional induction cell wall-modifying enzyme genes, such GLYCOSYL HYDROLASE 9Bs, PECTATE LYASE LIKEs EXPANSINs. Furthermore, chemical composition wall monosaccharides markedly different mutant. These data together suggest modifies properties, may facilitate reconnection. PpWOX13L complements mutant, molecular function conserved between mosses This provides insights into conservation functional diversification gene family during land plant evolution.

Language: Английский

Citations

101
Discovering the drivers of clonal hematopoiesis DOI Creative Commons
Oriol Pich, Iker Reyes-Salazar, Abel González-Pérez

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 23, 2022

Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) drive clonal hematopoiesis (CH). While some CH drivers have been identified, the compendium of all able upon mutations HSCs remains incomplete. Exploiting signals positive selection blood somatic may be an effective way identify driver genes, analogously cancer. Using tumor sample blood/tumor pairs as reference, we across more than 12,000 donors from two large cancer genomics cohorts. The application IntOGen, discovery pipeline, both cohorts, and 24,000 targeted sequenced samples yields list close 70 with CH, available at http://www.intogen.org/ch . This approach recovers known discovers other candidates.

Language: Английский

Citations

66
RNA polymerase II clusters form in line with surface condensation on regulatory chromatin DOI
Agnieszka Pancholi, Tim Klingberg, Weichun Zhang

et al.

Molecular Systems Biology, Journal Year: 2021, Volume and Issue: 17(9)

Published: Sept. 1, 2021

Language: Английский

Citations

64