Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication DOI Open Access
Helen Ray-Jones,

Zeji Song,

Lai Ting Chan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 7, 2023

Abstract Gene enhancers often form long-range contacts with promoters, but it remains unclear if enhancer activity and their chromosomal are mediated by the same DNA sequences recruited factors. We studied effects of expression quantitative trait loci (eQTLs) on promoter in primary monocytes isolated from 34 individuals. Using eQTL-Capture Hi-C a Bayesian approach considering both intra- inter-individual variation, we initially detected 19 eQTLs associated enhancer-eGene contacts, most which also accessibility activity. Capitalising these shared effects, devised multi-modality strategy, identified 629 “trimodal QTLs” jointly accessibility, eGene contact, gene expression. Causal mediation analysis CRISPR interference revealed causal relationships between three modalities. Many QTLs overlapped disease susceptibility influenced predicted binding myeloid transcription factors, including SPI1, GABPB STAT3. Additionally, variant PCK2 contact directly disrupted CTCF motif impacted insulation downstream enhancers. Jointly, our findings suggest an inherent genetic link connectivity relevance for human disease, highlight role genetically-determined chromatin boundaries control.

Language: Английский

Individual transcription factors modulate both the micromovement of chromatin and its long-range structure DOI Creative Commons
Haitham A. Shaban, Elias T. Friman, Cédric Deluz

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(18)

Published: April 22, 2024

The control of eukaryotic gene expression is intimately connected to highly dynamic chromatin structures. Gene regulation relies on activator and repressor transcription factors (TFs) that induce local opening closing. However, it unclear how nucleus-wide organization responds dynamically the activity specific TFs. Here, we examined two TFs with opposite effects accessibility modulate dynamics nucleus-wide. We combine high-resolution diffusion mapping dense flow reconstruction correlation in living cells obtain an imaging-based, nanometer-scale analysis processes long-range coordinated movements both show either individual transcriptional (CDX2) or (SIX6) large numbers binding sites increases mobility nucleus-wide, yet they coherent motions at micron scale. Hi-C higher-order structures shows induction pioneer factor CDX2 leads changes interactions distribution A B compartments, thus relating micromovement compartmental Given inhibition initiation elongation by RNA Pol II has a partial impact global induced CDX2, suggest overexpression alters structure dependently independently transcription. Our biophysical sequence-specific can influence multiple architectural levels, arguing brought alter its organization.

Language: Английский

Citations

7
Genetic coupling of enhancer activity and connectivity in gene expression control DOI Creative Commons
Helen Ray-Jones, Changmin Sung, Lai Ting Chan

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 27, 2025

Abstract Gene enhancers often form long-range contacts with promoters, but it remains unclear if the activity of and their chromosomal are mediated by same DNA sequences recruited factors. Here, we study effects expression quantitative trait loci (eQTLs) on enhancer promoter in primary monocytes isolated from 34 male individuals. Using eQTL-Capture Hi-C a Bayesian approach considering both intra- inter-individual variation, initially detect 19 eQTLs associated enhancer-eGene contacts, most which also associate accessibility activity. Capitalising these shared effects, devise multi-modality strategy, identifying 629 “trimodal QTLs” jointly accessibility, eGene contact, gene expression. Causal mediation analysis CRISPR interference reveal causal relationships between three modalities. Many detected QTLs overlap disease susceptibility influence predicted binding myeloid transcription factors, including SPI1, GABPB STAT3. Additionally, variant PCK2 contact directly disrupts CTCF motif impacts insulation downstream enhancers. Jointly, our findings suggest an inherent genetic coupling connectivity control relevant to human highlight regulatory role genetically determined chromatin boundaries.

Language: Английский

Citations

0
Pioneer factors outline chromatin architecture DOI Creative Commons

Juan Carlos Gómora-García,

Mayra Furlan-Magaril

Current Opinion in Cell Biology, Journal Year: 2025, Volume and Issue: 93, P. 102480 - 102480

Published: Feb. 12, 2025

Language: Английский

Citations

0
Genome-wide analysis of the biophysical properties of chromatin and nuclear proteins in living cells with Hi-D DOI
César Augusto Valades-Cruz, Roman Barth, Marwan Abdellah

et al.

Nature Protocols, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 28, 2024

Language: Английский

Citations

2
Tracing the Chromatin: From 3C to Live-Cell Imaging DOI Creative Commons
Arianna N. Lacen, Hui-Ting Lee

Chemical & Biomedical Imaging, Journal Year: 2024, Volume and Issue: 2(10), P. 659 - 682

Published: June 25, 2024

Chromatin organization plays a key role in gene regulation throughout the cell cycle. Understanding dynamics governing accessibility of chromatin is crucial for insight into mechanisms regulation, DNA replication, and division. Extensive research has been done to track explain how cells function diseases develop, hope this knowledge leading future therapeutics utilizing proteins or drugs that modify expression disease-related genes. Traditional methods studying movement relied on cross-linking spatially adjacent sections hybridizing fluorescent probes chromosomal loci then constructing dynamic models from static data collected at different time points. While these traditional are fruitful understanding fundamental aspects organization, they limited by their invasive sample preparation protocols diffraction-limited microscope resolution. These limitations have challenged modern based high- super-resolution microscopy specific labeling techniques derived targeting tools. more sensitive less than methods, therefore allowing researchers compactness, even distance rate domain detail real time. This review highlights selection recently developed tracking applications fixed live cells.

Language: Английский

Citations

1
Rethinking chromatin accessibility: from compaction to dynamic interactions DOI Creative Commons

Tom Fillot,

Davide Mazza

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 90, P. 102299 - 102299

Published: Dec. 19, 2024

Language: Английский

Citations

1
Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication DOI Open Access
Helen Ray-Jones,

Zeji Song,

Lai Ting Chan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 7, 2023

Abstract Gene enhancers often form long-range contacts with promoters, but it remains unclear if enhancer activity and their chromosomal are mediated by the same DNA sequences recruited factors. We studied effects of expression quantitative trait loci (eQTLs) on promoter in primary monocytes isolated from 34 individuals. Using eQTL-Capture Hi-C a Bayesian approach considering both intra- inter-individual variation, we initially detected 19 eQTLs associated enhancer-eGene contacts, most which also accessibility activity. Capitalising these shared effects, devised multi-modality strategy, identified 629 “trimodal QTLs” jointly accessibility, eGene contact, gene expression. Causal mediation analysis CRISPR interference revealed causal relationships between three modalities. Many QTLs overlapped disease susceptibility influenced predicted binding myeloid transcription factors, including SPI1, GABPB STAT3. Additionally, variant PCK2 contact directly disrupted CTCF motif impacted insulation downstream enhancers. Jointly, our findings suggest an inherent genetic link connectivity relevance for human disease, highlight role genetically-determined chromatin boundaries control.

Language: Английский

Citations

3