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

Defining Mechanistic Links Between the Non-Coding Variant rs17673553 in CLEC16A and Lupus Susceptibility DOI Open Access
Harikrishna Reddy Rallabandi, Manish Kumar Singh, Loren L. Looger

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 314 - 314

Published: Jan. 1, 2025

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by widespread inflammation and autoantibody production. Its development progression involve genetic, epigenetic, environmental factors. Although genome-wide association studies (GWAS) have repeatedly identified susceptibility signal at 16p13, its fine-scale source functional mechanistic role in SLE remain unclear. We used bioinformatics to prioritize likely variants validated the top candidate through various experimental techniques, including clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing B cells. To assess impact of proposed causal variant C-type lectin domain family 16, member A (CLEC16A), we compared autophagy levels between wild-type (WT) knock-out (KO) Systematic analysis highly conserved non-coding intronic rs17673553, with risk allele apparently affecting enhancer function regulating several target genes, CLEC16A itself. Luciferase reporter assays followed chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) this activity, demonstrating that increases binding histone marks (H3K27ac H3K4me1), CTCF-binding factor, key immune transcription factors (GATA3 STAT3). Knock-down GATA3 STAT3 via siRNA led significant decrease expression. These regulatory effects on gene were further confirmed using CRISPR-based CRISPR-dCas9-based epigenetic activation/silencing. Functionally, WT cells exhibited higher starvation-induced KO cells, highlighting rs17673553 locus regulation. findings suggest locus—particularly allele—drives allele-specific modifications multiple factors, thereby mechanistically expression autophagy-associated This mechanism could potentially explain SLE, underlie 16p13.

Language: Английский

Citations

0
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