Steroid receptor-assisted loading modulates transcriptional responses in prostate cancer cells DOI Creative Commons

Johannes Hiltunen,

Laura Helminen, Niina Aaltonen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 15, 2024

ABSTRACT Steroid receptors are involved in a wide array of crosstalk mechanisms that regulate diverse biological processes, with significant implications diseases, particularly cancers. In prostate cancer, indirect between androgen receptor (AR) and glucocorticoid (GR) is well-documented, where GR replaces antiandrogen-inactivated AR becoming the disease driver. However, existence impact direct chromatin cancer have remained elusive. Our genome-wide investigations reveal activation significantly expands binding. Mechanistically, induces remodeling closed sites, facilitating binding to inaccessible sites. Importantly, coactivation results distinct transcriptional responses at both cell population single-cell levels. Intriguingly, pathways affected by these changes generally associated improved patient survival. Thus, yields markedly different outcomes from known role circumventing blockade antiandrogens.

Язык: Английский

AR-V7 condensates drive androgen-independent transcription in castration resistant prostate cancer DOI Open Access
Shabnam Massah,

Nicholas Pinette,

Jane Foo

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Summary Biomolecular condensates organize cellular environments and regulate key processes such as transcription. We previously showed that full-length androgen receptor (AR-FL), a major oncogenic driver in prostate cancer (PCa), forms nuclear upon stimulation androgen-sensitive PCa cells. Disrupting these impairs AR-FL transcriptional activity, highlighting their functional importance. However, resistance to deprivation therapy often leads castration-resistant (CRPC), driven by constitutively active splice variants like AR variant 7 (AR-V7). The mechanisms underlying AR-V7’s role CRPC remain unclear. In this study, we characterized the condensate-forming ability of AR-V7 compared its phase behavior with across spectrum models vitro conditions. Our findings indicate context can influence capacity. Unlike AR-FL, spontaneously absence functions independently models. requires higher concentration form condensates, both contexts . further reveal drives transcription via condensate-dependent condensate-independent mechanisms. Using an mutant incapable forming while retaining localization DNA-binding ability, regime activates part KRAS pathway Genes under were found harbor significantly numbers AR-binding sites exhibited boosted expression response AR-V7. These uncover unrecognized condensate formation driving programs shed light on unique contribution progression. Highlights androgens mediates independent Condensate-dependent enables genes exhibit exponential increase expression, number binding potentially playing reliance formation. Graphical Abstract

Язык: Английский

Процитировано

0
Acute Activation of Genes Through Transcriptional Condensates Impact Non-target Genes in a Chromatin Domain DOI Open Access

Darshika Bohra,

Zubairul Islam,

Sundarraj Nidharshan

и другие.

Опубликована: Март 19, 2025

Transcription activation of genes by estrogen is driven enhancers, which are often located within the same Topologically Associating Domain (TAD) as non-targeted promoters. We investigated how acute enhancer-driven affects neighbouring non-target TAD. Using single-molecule RNA FISH (smFISH), we tracked transcription TFF1 (enhancer-targeted) and TFF3 (non-targeted) during stimulation. observed mutually exclusive expression patterns: peaked at 1 hour, while reached its peak 3 hours, after ’s had diminished. Chromatin looping data indicated that enhancer loops with but not , suggesting upregulation due to direct enhancer-promoter interactions. CRISPR deletion 1,6-hexanediol (HD) exposure revealed enhancer:promoter undergo Liquid-Liquid Phase Separation (LLPS), sequesters transcriptional machinery inhibits expression. As signalling wanes or LLPS disrupted, declines increases. Our findings reveal can indirectly influence genes, highlighting a dynamic shift in gene progresses.

Язык: Английский

Процитировано

0
Implication of androgen receptor gene dysfunction in human Müllerian duct anomalies DOI
Lin Li, Shuya Chen, Shenghui Li

и другие.

European Journal of Obstetrics & Gynecology and Reproductive Biology, Год журнала: 2024, Номер 294, С. 198 - 205

Опубликована: Янв. 28, 2024

Язык: Английский

Процитировано

2
Local DNA compaction creates TF-DNA clusters that enable transcription DOI Creative Commons
Noémie M. Chabot, Ramya Purkanti,

Alessia Del Panta Ridolfi

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 25, 2024

Transcription factor (TF) clusters have been suggested to facilitate transcription. The mechanisms driving the formation of TF and their impact on transcription, however, remain largely unclear. This is mostly due lack a tractable system. Here, we exploit transcriptional activation mir430 in zebrafish embryos simultaneously follow dynamic large Nanog cluster, underlying DNA, transcription output by live imaging at high temporal spatial resolution. We find that cluster can support requires local DNA compaction. brings more Nanog-binding sites into therefore Nanog. Importantly, stabilizes this TF-DNA which emphasizes interdependent relationship between TFs dynamics formation. Once Nanog-DNA locus reaches maximum amount Nanog, begins. locus-intrinsic feature, shows self-regulates recruitment an optimal Our study supports model endogenous positively form through combination binding

Язык: Английский

Процитировано

2
Advances in the understanding of androgen receptor structure and function and in the development of next-generation AR-targeted therapeutics DOI

Wendy Effah,

Marjana Khalil,

Dong‐Jin Hwang

и другие.

Steroids, Год журнала: 2024, Номер 210, С. 109486 - 109486

Опубликована: Авг. 5, 2024

Язык: Английский

Процитировано

2
Roles of intrinsically disordered protein regions in transcriptional regulation and genome organization DOI
Jiapei Miao, Shasha Chong

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 90, С. 102285 - 102285

Опубликована: Дек. 3, 2024

Язык: Английский

Процитировано

1
Regulatory mechanisms of steroid hormone receptors on gene transcription through chromatin interaction and enhancer reprogramming DOI
Ge Sun,

Chunguang Zhao,

Jing Han

и другие.

Cellular Oncology, Год журнала: 2024, Номер 47(6), С. 2073 - 2090

Опубликована: Ноя. 14, 2024

Язык: Английский

Процитировано

1
Allosteric communications between domains of nuclear receptors DOI Creative Commons
Fraydoon Rastinejad

Steroids, Год журнала: 2024, Номер unknown, С. 109551 - 109551

Опубликована: Дек. 1, 2024

Nuclear receptors (NRs) regulate gene expression in response to hormonal signals, influencing diverse physiological processes and diseases. Structural dynamics investigations based on X-ray crystallography, cryo-electron microscopy (cryo-EM), hydrogen-deuterium exchange mass spectrometry, molecular simulations, have significantly deepened our understanding of the conformational states, dynamics, interdomain interactions multi-domain NRs. studies examined heterodimeric complexes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) with retinoid X alpha (RXRα), liver beta (LXRβ) RXRα, retinoic acid (RARβ) well homodimers like hepatic nuclear factor 4 (HNF-4α), androgen (AR), glucocorticoid (GR). These highlight critical allosteric communication between ligand-binding domains (LBDs) DNA-binding (DBDs), emphasizing roles flexible hinge regions N-terminal segments adapting DNA configurations. Both non-steroid heterodimers exhibit robust connections that mediate signaling. For instance, AR demonstrates three distinct states underscore its dynamic behavior, while GR exhibits unique ligand-dependent domain shaping The collective findings so far suggest a conserved mechanism cross-domain across NR family. Supported by complementary biophysical, spectroscopic, mutagenesis, computational studies, this body research has elucidated nature domain-domain interfaces their pivotal regulating transcriptional activity steroid receptors.

Язык: Английский

Процитировано

1
The microtubule regulator EFA-6 forms spatially restricted cortical foci dependent on its intrinsically disordered region and interactions with tubulins DOI Creative Commons

Anjali Sandhu,

Xiaohui Lyu,

Xinghaoyun Wan

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 14, 2024

ABSTRACT Microtubules (MTs) are dynamic components of the cytoskeleton and play essential roles in morphogenesis maintenance tissue cell integrity. Despite recent advances understanding MT ultrastructure, organization, growth control, how cells regulate organization at cortex remains poorly understood. The EFA-6/EFA6 proteins recently identified membrane-associated that inhibit cortical dynamics. Here, combining visualization endogenously tagged C. elegans EFA-6 with genetic screening, we uncovered tubulin-dependent regulation patterning. In mature epidermal epithelium, forms punctate foci specific regions apical cortex, dependent on its intrinsically disordered region (IDR). We further show IDR is sufficient to form biomolecular condensates vitro . screens for mutants altered GFP::EFA-6 localization, a novel gain-of-function (gf) mutation an α-tubulin tba-1 induces ectopic multiple types. tba-1(gf) animals exhibit temperature-sensitive embryonic lethality, which partially suppressed by efa-6(lf) , indicating interaction between tubulins important normal development. TBA-1(gf) shows reduced incorporation into filamentous MTs but has otherwise mild effects cellular organization. ability trigger formation requires β-tubulin TBB-2 chaperon EVL-20/Arl2. tba-1(gf)- induced display slower turnover, contain MT-associated protein TAC-1/TACC, require MTED. Our results reveal crosstalk regulators vivo Highlights regulator spatially restricted N-terminal (IDR) droplet Tubulins via elimination domain tubulin heterodimer function turnover recruit TAC-1/TACC

Язык: Английский

Процитировано

0
Acute Activation of Genes Through Transcriptional Condensates Impact Non-target Genes in a Chromatin Domain DOI Creative Commons

Darshika Bohra,

Zubairul Islam,

Sundarraj Nidharshan

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 26, 2024

Abstract Transcription activation of genes by estrogen is driven enhancers, which are often located within the same Topologically Associating Domain (TAD) as non-targeted promoters. We investigated how acute enhancer-driven affects neighbouring non-target TAD. Using single-molecule RNA FISH (smFISH), we tracked transcription TFF1 (enhancer-targeted) and TFF3 (non-targeted) during stimulation. observed mutually exclusive expression patterns: peaked at 1 hour, while reached its peak 3 hours, after ’s had diminished. Chromatin looping data indicated that enhancer loops with but not , suggesting upregulation due to direct enhancer-promoter interactions. CRISPR deletion 1,6-hexanediol (HD) exposure revealed enhancer:promoter undergo Liquid-Liquid Phase Separation (LLPS), sequesters transcriptional machinery inhibits expression. As signalling wanes or LLPS disrupted, declines increases. Our findings reveal can indirectly influence genes, highlighting a dynamic shift in gene progresses.

Язык: Английский

Процитировано

0