Biology subjects

Shome, S.

Publications and source records attributed to Shome, S..

3 recordsLinked to original sources

bioRxiv2026

Sequence-Based Prioritization of Promoter Regulatory Variants in Colorectal Cancer Using a DNA Foundation Model

Noncoding regulatory variants contribute to colorectal cancer (CRC) susceptibility, yet their functional interpretation remains difficult.This is mainly attributed to regulatory effects being context-dependent and most noncoding regions lack reliable genomic annotations. We have developed a computational framework that aids in prioritizing promoter-associated variants using Evo2, a large-scale autoregressive DNA foundation model. In the framework, variants were mapped to promoter regions ({+/-}1,024 bp) across [~]1,250 CRC-associated genes and scored using Evo2-derived delta scores, the difference in sequence probability between reference and alternate alleles. Promoter variants showed greater predicted regulatory impact than non-promoter variants (median delta = 0.015 vs. 0.002; overall mean = 0.018, SD = 0.011). Applying a distributional threshold (delta > 0.020; top [~]25%) identified 287 high-impact variants across 198 CRC-associated genes. These genes were enriched in CRC-relevant pathways such as Wnt signaling, p53 signaling, and cell cycle regulation and 36.4% (72/198) overlapped known cancer genes (2.3-fold enrichment, p = 8.7x10-6). Independent validation showed high-impact variants were enriched at CRC GWAS loci and overlapped transcription factor binding sites ([~]32%) and motif-disrupting positions ([~]21%), supporting their functional relevance. Together, these results show that sequence-based foundation models can scalably prioritize noncoding regulatory candidates in CRC without supervised training or predefined annotations.

bioinformatics↗

bioRxiv2023

ITPK1 regulates jasmonate-controlled root development in Arabidopsis thaliana

Jasmonic acid (JA) is a plant hormone that regulates a plethora of physiological processes including immunity and development and is perceived by the F-Box protein, Coronatine-insensitive protein 1(COI1). The discovery of inositol phosphates (InsPs) in the COI1 receptor complex highlights their role in JA perception. InsPs are phosphate-rich signaling molecules that control many aspects of plant physiology. Inositol pyrophosphates (PP-InsPs) are diphosphate containing InsP species of which InsP7 and InsP8 are the best characterized ones. Different InsP and PP-InsP species are linked with JA-related plant immunity. However, role of PP-InsP species in regulating JA-dependent developmental processes are poorly understood. Recent identification of ITPK1 kinase responsible for the production of 5-InsP7 from InsP6 in planta provides a platform to interrogate possible involvement of ITPK-derived InsP species in JA-related plant development. Herein this study, we report that ITPK1-defective plants exhibit increased root growth inhibition to bioactive JA treatment. The itpk1 plants also show increased lateral root density when treated with JA. Notably, JA treatment does not induce ITPK1 protein level. Gene expression analyses revealed that JA-biosynthetic genes are not differentially expressed in the ITPK1-deficient plants. We further demonstrate that genes encoding different JAZ repressor proteins are severely downregulated in the ITPK1-defective plants. Taken together, our study highlights the role of ITPK1 in regulating JA-dependent root architecture development through controlling expression of different JAZ repressor proteins.

plant biology↗

bioRxiv2022

New Functions Identified for HIV gp120 with the New ProtSub Sequence Matching

The reduced cost of sequencing is leading to an explosive growth in the number of available sequences across diverse genomes, and for individual patients. Inferring meaningful functions of individual genes/proteins is lagging, which hinders the deeper understanding of biological function and evolution. Traditionally, protein function has been determined by time consuming experimental methods or by sequence matching that often does not agree with the experimental findings. We have significantly improved protein sequence matching, by accounting for inter-dependent amino acid substitutions observed within densely packed protein structures, which yields additional substitutions beyond those usually seen, with good matches to additional proteins, some having new functions, not identified by conventional sequence matching. In the current study, we have applied this approach to predict novel functions for the proteins from HIV. These newly found functional annotations are then manually reviewed and many are validated from the literature, here for the HIV envelope protein gp120. These new functions are both more specific as well as some being entirely novel functions. We also show statistically that on average our new functional annotations are more informative than those given by conventional substitution matrices such as BLOSUM62. These results suggest that the new ProtSub protein sequence matching that incorporates structural information generally yields better identifications of related proteins, which can have broader and often gains in identifying more specific functions

bioinformatics↗