Biology subjects

Iyer, M. S.

Publications and source records attributed to Iyer, M. S..

6 recordsLinked to original sources

bioRxiv2025

GenDiS3 database: census on prevalence of protein domain superfamilies of known structure in the entire sequence database

Despite the vast amount of sequence data available, a significant disparity exists between the number of protein sequences identified and the relatively few structures that have been resolved. This disparity highlights the challenge in structural biology to bridge the gap between sequence information and three-dimensional structural data, and the necessity for robust databases capable of linking distant homologues to known structures. Studies have indicated that there is a limited number of structural folds, despite the vast diversity of proteins. Hence, computational tools can enhance our ability to classify protein sequences, much before their structures are determined or their functions characterised, thereby bridging the gap between sequence and structural data. GenDiS is a repository with information on Genomic Distribution of protein domain superfamilies, involving a one-time computational exercise to search for trusted homologues of protein domains of known structures against the vast sequence database. We have updated this database employing advanced bioinformatics tools, including DELTA-BLAST for initial detection of hits and HMMSCAN for validation, significantly improving the accuracy of domain identification. Using these tools, over 151 million sequence homologues for 2060 superfamilies (SCOPe) were identified and 116 million out of them were validated as true positives. Through a case study on glycolysis-related enzymes, variations in domain architectures of these enzymes are explored, revealing evolutionary changes and functional diversity amongst these essential proteins. We present another case, LoG gene, where there one can tune-in and find significant mutations across the evolutionary lineage. The GenDiS database, GenDiS3, and the associated tools made available at https://caps.ncbs.res.in/gendis3/, offer a powerful resource for researchers in functional annotation and evolutionary studies. Database URL: https://caps.ncbs.res.in/gendis3/

bioinformatics↗

bioRxiv2022

A systems biology approach to disentangle the direct and indirect effects of global transcription factors on gene expression in Escherichia coli

Delineating the pleiotropic effects of global transcriptional factors (TFs) is critical in understanding the system-wide regulatory response in a particular environment. Currently, with the availability of genome-wide TF binding and gene expression data for Escherichia coli, several gene targets can be assigned to the global TFs albeit inconsistently. Here, using a systematic integrated approach with emphasis on metabolism, we characterize and quantify the direct effects as well as the growth-rate mediated indirect effects of global TFs using deletion mutants of FNR, ArcA, and IHF regulators under glucose fermentative condition. Apart from the previous known metabolite-TF interactions, we predicted with high confidence several novel interactions arising from the allosteric effects of the intracellular metabolites. Our combined experimental and compendium level computational analyses revealed the co-expressed genes regulated by these TFs as well as the coordination of the direct and indirect target gene expressions in the context of the economy of intracellular metabolites. Besides, we extended our analysis to combinatorial deletions of these TFs to determine their cross-talk effects as well as conserved patterns of regulatory interactions. Overall, this study leverages the fundamentals of TF-driven regulation which could serve as a better template for deciphering mechanisms underlying complex phenotypes.

systems biology↗

bioRxiv2022

Social deficits induced by pervasive environmental stressors are prevented by microbial or dopaminergic modulation

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglia and dopaminergic circuits in the brain, along with changes in the structure of the gut epithelium and microbiome. Importantly, DEP/MS-induced social deficits in males are prevented by shifting the gut microbiome by cross-fostering at birth and reversed by chemogenetic activation of the dopamine system.

neuroscience↗

bioRxiv2021

Mutant strains of Escherichia coli lacking global regulators, arcA and fis, demonstrate better growth fitness by pathway reprogramming under acetate metabolism

Global regulatory transcription factors play a significant role in controlling microbial metabolism under genetic and environmental perturbations. A systems-level effect of carbon sources such as acetate on microbial metabolism under disrupted global regulators has not been well established. Acetate is one of the substrates available in a range of nutrient niches such as the mammalian gut and high-fat diet. Therefore, investigating the study on acetate metabolism is highly significant. It is well known that the global regulators arcA and fis regulate acetate uptake genes in E. coli under glucose condition. In this study, we deciphered the growth and flux distribution of E.coli transcription regulatory knockout mutants {Delta}arcA, {Delta}fis and double deletion mutant, {Delta}arcAfis under acetate using 13C-Metabolic Flux Analysis which has not been investigated before. We observed that the mutants exhibited an expeditious growth rate (~1.2-1.6 fold) with a proportionate increase in acetate uptake rates compared to the wild-type. 13C-MFA displayed the distinct metabolic reprogramming of intracellular fluxes, which conferred an advantage of faster growth with better carbon usage in all the mutants. Under acetate metabolism, the mutants exhibited higher fluxes in the TCA cycle (~18-90%) and lower gluconeogenesis flux (~15-35%) with the proportional increase in growth rate. This study reveals a novel insight by stating the sub-optimality of the wild-type strain grown under acetate substrate aerobically. These mutant strains efficiently oxidize acetate to acetyl-CoA and therefore are potential candidates that can serve as a precursor for the biosynthesis of isoprenoids, biofuels, vitamins and various pharmaceutical products. ImportanceUnravelling the role of global regulatory genes on microbial metabolism of substrates available in various growth niche is important. Studies have shown that the global transcriptional regulators arcA and fis, under glucose availability, suppress the acetate uptake genes indicating a link between nutrient source and gene regulatory control. This work is focused on deciphering the influence of these regulators on acetate metabolism in E.coli. Growth studies using knockout strains ({Delta}arcA, {Delta}fis and {Delta}arcAfis) and 13C Metabolic flux analysis defined precise metabolic phenotypes under acetate metabolism. Interestingly, the mutants showed metabolic readjustment to facilitate optimal biomass requirements and a better balance between energy and precursor synthesis, resulting in better growth, which lacked in the wild-type strain. The outcomes of this study will be leveraged in understanding the regulatory control under various nutrient shifts.

microbiology↗

bioRxiv2020

Global transcriptional regulators fine-tune the translational and metabolic machinery in Escherichia coli under anaerobic fermentation

Complex regulatory interactions between genetic and metabolic networks together confer robustness against external and internal perturbations in an organism such as Escherichia coli. In balanced exponential growth, this robustness is attributed to cost-effective metabolism by means of efficient resource allocation coordinated by the interplay of global transcriptional regulators with growth-rate dependent machinery. Here, we reappraise the role of global transcriptional regulators FNR, ArcA and IHF, integral to sustaining proteome-efficiency in anaerobic fermentative conditions, fundamental for optimal growth of E. coli. We reveal at the transcriptome and metabolome level, that absence of these global regulators ensued a disruption of nitrogen homeostasis, overexpression of otherwise unnecessary or hedging genes and impairment in core bottleneck steps and amino acid metabolism. Notably, our findings emphasize their importance in optimizing the metabolic proteome resources essential for rapid exponential growth. Consequentially, the perturbations in the metabolic proteome as a result of deletion of global regulators unbalances the ribosomal proteome share imposing a high translation program, though at the expense of lowered efficiency. We illustrate that disruption of this inherent trade-off between metabolic and ribosomal proteomic investment eventually culminate to lowered growth rates. Despite no changes in gene expression related to glucose import, our findings elucidate that the accumulations of intracellular metabolites directly modulated by growth rate, negatively impacts the glucose uptake. Our results employing the proteome allocation theory and quantitative experimental measurements, suffices to explain the physiological consequences of altered translational and metabolic efficiency in the cell, driven by the loss of these global regulators.

systems biology↗

bioRxiv2020

Elucidating the regulatory role of CRP in coordinating protein biosynthesis machinery with metabolism that defines growth optimality in Escherichia coli

Evolution entails the orchestration of cellular resources together with mutations to achieve fitter phenotypes. Here, we determined the system-wide pleiotropic effects that redress the significant perturbations caused by the deletion of global transcriptional regulator CRP in Escherichia coli when evolved in the presence of glucose. We elucidated that absence of CRP results in alterations in key metabolic pathways instrumental for the precise functioning of protein biosynthesis machinery that subsequently corroborated with intracellular metabolite profiles. Apart from acquiring mutations in the promoter of glucose transporter ptsG, the evolved populations recovered the metabolic pathways to their pre-perturbed state with amelioration of protein biosynthesis machinery coupled with fine-tuned proteome re-allocation that enabled growth recovery. However, ineffective utilization of carbon towards biomass as perceived from ATP maintenance flux and costly amino acid accumulations poses a limitation. Overall, we comprehensively illustrate the genetic and metabolic adjustments underlying adaptive evolvability, fundamental for understanding the growth physiology.

systems biology↗