Biology subjects

Kaalia, R.

Publications and source records attributed to Kaalia, R..

2 recordsLinked to original sources

bioRxiv2025

The 9p21.3 Coronary Artery Disease Risk Locus Modulates Vascular Cell-State Transitions via Enhancer-Driven Regulation of MTAP

The 9p21.3 locus is the strongest genetic association with coronary artery disease (CAD), yet its causal mechanisms remain unresolved. We map the regulatory architecture of 9p21.3 in disease-relevant vascular cells, identifying 12 enhancers within the CAD risk haplotype that respond dynamically to inflammatory and metabolic stress in fibroblasts and smooth muscle cells. These activated states are enriched for CAD heritability, implicating stress-responsive vascular wall cells in disease pathophysiology. Dense CRISPRi tiling integrated with fine-mapping and genomic constraint across >500,000 individuals nominates MTAP as the effector gene, with rs1537371 as a likely causal variant. Perturbation and multi-modal analyses show that MTAP loss induces pro-fibrotic and angiogenic programs and sensitizes vascular cells to TGF-{beta}-driven pathological transitions. Our findings reveal a vascular-specific enhancer network through which noncoding variation at 9p21.3 modulates CAD risk via MTAP--a previously unrecognized regulator of vascular remodeling located 269 kb from the risk haplotype. HighlightsO_LI9p21.3 CAD risk locus harbors 12 functional enhancers active in vascular wall cell types C_LIO_LICAD heritability is enriched in stressed vascular fibroblasts and smooth muscle cells C_LIO_LIHigh-resolution CRISPRi-MAC-seq maps 9p21.3 enhancer-gene and SNP-gene interactions C_LIO_LIMTAP identified as a causal effector gene regulated by 9p21.3 fine-mapped and constrained variants C_LIO_LIMTAP modulates TGF-{beta}-driven pathological vascular cell transitions C_LI

genomics↗

bioRxiv2019

Refining modules to determine functionally significant clusters in molecular networks

Module detection algorithms relying on modularity maximization suffer from an inherent resolution limit that hinders detection of small topological modules, especially in molecular networks where most biological processes are believed to form small and compact communities. We propose a novel modular refinement approach that helps finding functionally significant modules of molecular networks. The module refinement algorithm improves the quality of topological modules in protein-protein interaction networks by finding biologically functionally significant modules. The algorithm is based on the fact that functional modules in biology do not necessarily represent those corresponding to maximum modularity. Larger modules corresponding to maximal modularity are incrementally re-modularized again under specific constraints so that smaller yet topologically and biologically valid modules are recovered. We show improvement in quality and functional coverage of modules using experiments on synthetic and real protein-protein interaction networks. Results were also compared with six existing methods available for clustering biological networks. In conclusion, the proposed algorithm finds smaller but functionally relevant modules that are undetected by classical quality maximization approaches for modular detection. The refinement procedure helps to detect more functionally enriched modules in protein-protein interaction networks, which are also more coherent with functionally characterised gene sets.

bioinformatics↗