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

et al.

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

Published: Sept. 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.

Language: Английский

Epigenetic pioneering by SWI/SNF family remodelers DOI Creative Commons
Kami Ahmad, Sandipan Brahma, Steven Henikoff

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(2), P. 194 - 201

Published: Nov. 27, 2023

In eukaryotic genomes, transcriptional machinery and nucleosomes compete for binding to DNA sequences; thus, a crucial aspect of gene regulatory element function is modulate chromatin accessibility transcription factor (TF) RNA polymerase binding. Recent structural studies have revealed multiple modes TF engagement with nucleosomes, but how initial "pioneering" results in steady-state further II (RNAPII) has been unclear. Even less well understood distant sites open interact one another, such as when developmental enhancers activate promoters release RNAPII productive elongation. Here, we review evidence the centrality conserved SWI/SNF family nucleosome remodeling complexes, both pioneering mediating enhancer-promoter contacts. Consideration unwrapping ATP hydrolysis activities together their architectural features, may reconcile occupancy rapid dynamics observed by live imaging.

Language: Английский

Citations

24
Genome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells DOI Creative Commons
Riccardo Calandrelli, Xingzhao Wen, John Lalith Charles Richard

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 16, 2023

Abstract The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether architecture modulates spatial distribution of caRNA vice versa. Here, we generate a resource genome-wide RNA-DNA DNA-DNA contact maps human cells. These reveal chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined domains. Further, spreading constrained boundaries topologically associating (TADs), demonstrating role 3D structure modulating RNA. Conversely, stopping transcription or acute depletion induces thousands chromatin loops genome-wide. Activation suppression specific genes suppresses creates straddling these genes. Deletion caRNA-producing genomic sequence promotes that straddle interchromosomal target sequences this caRNA. data suggest feedback loop where which turn affects dynamic organization.

Language: Английский

Citations

23
Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release DOI
Turan Tufan, Gamze Cömertpay, Ambra Villani

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8007), P. 408 - 415

Published: March 13, 2024

Language: Английский

Citations

10
The phenylalanine-and-glycine repeats of NUP98 oncofusions form condensates that selectively partition transcriptional coactivators DOI
Jeong Hyun Ahn, Yiran Guo, Heankel Lyons

et al.

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
SWI/SNF-dependent genes are defined by their chromatin landscape DOI Creative Commons

Laura Basurto-Cayuela,

José A. Guerrero-Martínez, Elena Gómez-Marín

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113855 - 113855

Published: March 1, 2024

SWI/SNF complexes are evolutionarily conserved, ATP-dependent chromatin remodeling machines. Here, we characterize the features of SWI/SNF-dependent genes using BRM014, an inhibitor ATPase activity complexes. We find that is required to maintain accessibility and nucleosome occupancy for most enhancers but not promoters. needed expression with low medium levels have promoters (1) accessibility, (2) active histone marks, (3) high H3K4me1/H3K4me3 ratio, (4) nucleosomal phasing, (5) enrichment in TATA-box motifs. These mostly occupied by canonical Brahma-related gene 1/Brahma-associated factor (BAF) complex. surrounded mainly encode signal transduction, developmental, cell identity (with almost no housekeeping genes). Machine-learning models trained different characteristics their surrounding regulatory regions indicate landscape a determinant establishing dependency.

Language: Английский

Citations

7
Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes DOI
Jingwen Liao, Josephine Ho, Mannix J. Burns

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(8), P. 1780 - 1795.e6

Published: June 5, 2024

Language: Английский

Citations

7
RNA polymerase II promotes the organization of chromatin following DNA replication DOI Creative Commons
Susanne Bandau, Vanesa Álvarez, Hao Jiang

et al.

EMBO Reports, Journal Year: 2024, Volume and Issue: 25(3), P. 1387 - 1414

Published: Feb. 12, 2024

Abstract Understanding how chromatin organisation is duplicated on the two daughter strands a central question in epigenetics. In mammals, following passage of replisome, nucleosomes lose their defined positioning and transcription contributes to re-organisation. However, whether plays greater role organization DNA replication remains unclear. Here we analysed protein re-association with newly replicated upon inhibition using iPOND coupled quantitative mass spectrometry. We show that nucleosome assembly re-establishment most histone modifications are uncoupled from transcription. RNAPII acts promote hundreds proteins via pathways not observed steady-state chromatin. These include ATP-dependent remodellers, factors methyltransferases. also identify set repair may handle transcription-replication conflicts during normal human non-transformed cells. Our study reveals post-replication than previously anticipated.

Language: Английский

Citations

6
Nucleosome remodeler exclusion by histone deacetylation enforces heterochromatic silencing and epigenetic inheritance DOI
Rakesh Kumar Sahu,

Jothy Dhakshnamoorthy,

Shweta Jain

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(17), P. 3175 - 3191.e8

Published: Aug. 2, 2024

Language: Английский

Citations

6
Multifunctional histone variants in genome function DOI
Lee H. Wong, David J. Tremethick

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 13, 2024

Language: Английский

Citations

6
Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures DOI Creative Commons
Joshua Justice, Todd M. Greco, Josiah E. Hutton

et al.

Molecular Systems Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 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.

Language: Английский

Citations

0