Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures DOI Creative Commons
Joshua Justice, Todd M. Greco, Josiah E. Hutton

и другие.

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

Опубликована: Сен. 11, 2024

Abstract Huntington’s disease (HD) is a debilitating neurodegenerative disorder affecting an individual’s cognitive and motor abilities. HD caused by mutation in the huntingtin gene producing toxic polyglutamine-expanded protein (mHTT) leading to degeneration striatum cortex. Yet, molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect leveraging multi-epitope interaction assays, subcellular fractionation, thermal proteome profiling, genetic modifier assays. Use of human cell, mouse, fly models afforded capture distinct pools epitope-enriched tissue-dependent interactions linked dysregulated cellular pathways relevance. We established HTT association with nearly all subunits transcriptional regulatory Mediator complex (20/26), preferential enrichment MED15 tail domain. Using KO models, find modulates localization assembly Mediator. demonstrated striatal enriched functional regulators calcium homeostasis chromatin remodeling, whose relevance was supported modifiers Altogether, offer insights into tissue- localization-dependent (m)HTT functions pathobiology.

Язык: Английский

SWI/SNF Complex Connects Signaling and Epigenetic State in Cells of Nervous System DOI
Victor Chmykhalo, Roman V. Deev, Artemy T. Tokarev

и другие.

Molecular Neurobiology, Год журнала: 2024, Номер unknown

Опубликована: Июль 13, 2024

Язык: Английский

Процитировано

4
Long non-coding RNAs direct the SWI/SNF complex to cell type-specific enhancers DOI Creative Commons
James A. Oo, Timothy Warwick,

Katalin Pálfi

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 2, 2025

Abstract The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control. highly conserved ubiquitously expressed SWItch/Sucrose Non-Fermentable (SWI/SNF) complex plays a central role in cell type- context-dependent expression. Despite the absence defined recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open state. It does so while retaining ability to respond dynamically cellular signals. However, mechanisms that guide genomic targets have remained elusive. Here we demonstrate trans -acting long non-coding RNAs (lncRNAs) direct type-specific enhancers. preferentially lncRNAs these predominantly bind . Together they localize enhancers, many which are type-specific. Knockdown SWI/SNF- enhancer-bound causes redistribution away from concomitant differential spatially connected target genes. These lncRNA-SWI/SNF-enhancer networks support an enhancer hub model targeting. Our findings reveal competitively recruit SWI/SNF, providing dynamic layer control over accessibility, reinforcing their mediating activity

Язык: Английский

Процитировано

0
Basic Epigenetic Mechanisms DOI
James Davie, Hedieh Sattarifard, S Sudhakar

и другие.

Sub-cellular biochemistry/Subcellular biochemistry, Год журнала: 2025, Номер unknown, С. 1 - 49

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures DOI Creative Commons
Joshua Justice, Todd M. Greco, Josiah E. Hutton

и другие.

Molecular Systems Biology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Abstract Huntington’s disease (HD) is a debilitating neurodegenerative disorder affecting an individual’s cognitive and motor abilities. HD caused by mutation in the huntingtin gene producing toxic polyglutamine-expanded protein (mHTT) leading to degeneration striatum cortex. Yet, molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect leveraging multi-epitope interaction assays, subcellular fractionation, thermal proteome profiling, genetic modifier assays. The use of human cell, mouse, fly models afforded capture distinct pools epitope-enriched tissue-dependent interactions linked dysregulated cellular pathways relevance. We established HTT association with nearly all subunits transcriptional regulatory Mediator complex (20/26), preferential enrichment MED15 tail domain. Using KO models, find modulates localization assembly Mediator. demonstrated striatal enriched functional regulators calcium homeostasis chromatin remodeling, whose relevance was supported modifiers Altogether, offer insights into tissue- localization-dependent (m)HTT functions pathobiology.

Язык: Английский

Процитировано

0
Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal‐like and malignant urothelial cells DOI Creative Commons

R. Schlosser,

Florian Krumbach,

Eyleen Corrales

и другие.

Molecular Oncology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Bclaf1 Mediates Super-Enhancer-Driven Activation of POLR2A to Enhance Chromatin Accessibility in Nitrosamine-induced Esophageal Carcinogenesis DOI
Xiangjun Zhou,

X.E. Zhou,

Jun Li

и другие.

Journal of Hazardous Materials, Год журнала: 2025, Номер unknown, С. 138218 - 138218

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
The SWI/SNF PBAF complex facilitates REST occupancy at repressive chromatin DOI
Elena Grossi,

Christie B. Nguyen,

Saul Carcamo

и другие.

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
Proteasome Inhibition Reprograms Chromatin Landscape in Breast Cancer DOI Creative Commons
H. Karimi Kinyamu, Brian D. Bennett, James M. Ward

и другие.

Cancer Research Communications, Год журнала: 2024, Номер 4(4), С. 1082 - 1099

Опубликована: Апрель 16, 2024

Abstract The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear. Here, using integrative genomic analysis, we discovered unexpected reprogramming of chromatin landscape and RNA polymerase II (RNAPII) transcription initiation breast treated with inhibitor MG132. acquired dynamic changes accessibility at specific loci termed differentially open regions (DOCR). DOCRs decreased were promoter proximal exhibited unique architecture associated divergent RNAPII transcription. Conversely, increased primarily distal start sites enriched oncogenic superenhancers predominantly accessible non-basal subtypes. These findings describe mechanisms by which modulates intrinsic biology. Significance: Our study provides a strong basis for understanding exert anticancer effects. We find change during inhibition, are typically cancers.

Язык: Английский

Процитировано

3
The HIV-1 Transcriptional Program: From Initiation to Elongation Control DOI Creative Commons
Iván D’Orso

Journal of Molecular Biology, Год журнала: 2024, Номер unknown, С. 168690 - 168690

Опубликована: Июнь 1, 2024

A large body of work in the last four decades has revealed key pillars HIV-1 transcription control at initiation and elongation steps. Here, I provide a recount this collective knowledge starting with genomic elements (DNA nascent TAR RNA stem-loop) factors (cellular viral transactivator Tat), later transitioning to assembly regulation complexes, role chromatin structure. Compelling evidence support core transcriptional program regulated by sequential concerted action cellular Tat promote sustain elongation, highlighting efficiency small virus take over its host produce high levels required for replication. summarize new advances including use CRISPR-Cas9, genetic tools acute factor depletion, imaging study dynamics, bursting progression through multiple phases cycle. Finally, describe current challenges future major discuss areas that deserve more attention both bolster our basic open up therapeutic opportunities.

Язык: Английский

Процитировано

2
PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression DOI Creative Commons
Priya Mittal, Jacquelyn A. Myers, Raymond D. Carter

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Авг. 24, 2024

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% cancers. To gain insight into the mechanisms by which mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for subunit SMARCB1 to a genome-scale CRISPR–Cas9 depletion screen performed across 896 lines. We identify PHF6 as specifically essential RT survival and demonstrate that dependency on Phf6 extends Smarcb1-deficient cancers vivo. As either or can cause neurodevelopmental disorder Coffin-Siris syndrome, our findings suggest previously unrecognized functional link. co-localizes with at promoters, where it is maintenance an active state. show absence SMARCB1, loss disrupts recruitment stability residual complex members, collectively resulting promoters stalling RNA Polymerase II progression. Our work establishes mechanistic basis shared syndromic features CSS selective SMARCB1-mutant Here, authors SMARCB1-deficient Mechanistically, this study suggests regulatory role recruiting enable polymerase

Язык: Английский

Процитировано

2