Biology subjects

Ganapathiraju, M.

Publications and source records attributed to Ganapathiraju, M..

6 recordsLinked to original sources

bioRxiv2025

Discovery of Inverted Repeats and Palindromes in Viral Genomes

An inverted repeat (IR) in DNA is a sequence of nucleotides that is followed by its complementary bases but in reverse order, occurring on the same strand (e.g., TCACCGCGGTGA). If the two complementary sequences occur one after the other without other bases between them, they are referred to as DNA palindromes. IRs could form hairpin and cruciform secondary structures, which endanger genomic stability. They are found to be prevalent in viral DNA at origins of replication, and they play a crucial role in various biological processes including gene silencing, duplication, and genomic evolution. IRs have been less explored, which stems from the scarcity of sequence analysis tools allowing accurate detection on large viral genome data. Here, using the Biological Language Modeling Toolkit (BLMT), we analyzed 14 thousand viral genomes for occurrences of IRs, resulting in the identification of over 19 million IRs longer than 20 bases, including 134 IRs that are 2000 bases long, and around 1,300 IRs per virus.

bioinformatics↗

bioRxiv2023

Pathogenic mechanisms underlying adverse neurodevelopmental outcome in congenital heart disease

Poor neurodevelopment is often observed with congenital heart disease (CHD), especially with mutations in chromatin modifiers. Here analysis of mice with hypoplastic left heart syndrome (HLHS) arising from mutations in Sin3A associated chromatin modifier Sap130, and adhesion protein Pcdha9, revealed neurodevelopmental and neurobehavioral deficits reminiscent of those in HLHS patients. Microcephaly was associated with impaired cortical neurogenesis, mitotic block, and increased apoptosis. Transcriptional profiling indicated dysregulated neurogenesis by REST, altered CREB signaling regulating memory and synaptic plasticity, and impaired neurovascular coupling modulating cerebral blood flow. Many neurodevelopmental/neurobehavioral disease pathways were recovered, including autism and cognitive impairment. These same pathways emerged from genome-wide DNA methylation and Sap130 chromatin immunoprecipitation sequencing analyses, suggesting epigenetic perturbation. Mice with Pcdha9 mutation or forebrain-specific Sap130 deletion without CHD showed learning/memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation and suggest new avenues for therapy.

developmental biology↗

bioRxiv2022

GPX4-associated Sedaghatian Type Spondylometaphyseal Dysplasia: A Protein Interactome Perspective

Spondylometaphyseal dysplasia, Sedaghatian type (SMDS) is a rare and lethal skeletal dysplasia inherited in an autosomal recessive manner and caused by mutations in GPX4. In order to expand the functional landscape of this poorly studied disorder and accelerate the discovery of biologically insightful and clinically actionable targets, we constructed SMDS-centric and GPX4-centric protein-protein interaction (PPI) networks, augmented with novel protein interactors predicted by our HiPPIP algorithm. The SMDS-centric networks included those that showed the interconnections of GPX4 with other putative SMDS-associated genes and genes associated with other skeletal dysplasias. The GPX4-centric network showed the interconnections of GPX4 with genes whose perturbation has been known to affect GPX4 expression. We discovered that these networks either contained or were enriched with genes associated with specific SMDS pathophenotypes, tissue-naive/fetus-specific functional modules and genes showing elevated expression in brain and/or testis similar to GPX4. We identified 7 proteins as novel interactors of GPX4 (APBA3, EGR4, FUT5, GAMT, GTF2F1, MATK and ZNF197) and showed their potential biological relevance to GPX4 or SMDS. Comparative transcriptome analysis of expression profiles associated with chondroplasia and immune-osseous dysplasia versus drug-induced profiles revealed 11 drugs that targeted the neighborhood network of GPX4 and other putative SMDS-associated genes. Additionally, resveratrol, which is currently being tested against a skeletal dysplasia in a clinical trial, was identified as another potential candidate based on the proximity of its targets to GPX4.

developmental biology↗

bioRxiv2022

Drug Contraindications in Comorbid Diseases: a Protein Interactome Perspective

Adverse drug reactions (ADRs) are leading causes of death and drug withdrawals and frequently cooccur with comorbidities. However, systematic studies on the effects of drugs in comorbidities are lacking. Drug interactions with the cellular protein-protein interaction (PPI) network give rise to ADRs. We selected 6 comorbid disease pairs, identified the drugs used in the treatment of the individual diseases A and B- 44 drugs in anxiety and depression, 128 in asthma and hypertension, 48 in chronic obstructive pulmonary disease and heart failure, 58 in type 2 diabetes and obesity, 58 in Parkinsons disease and schizophrenia, and 84 in rheumatoid arthritis and osteoporosis - and categorized them based on whether they aggravate the comorbid condition. We constructed drug target networks (DTNs) and examined their enrichment among genes in disease A/B PPI networks, expressed across 53 tissues and involved in ~1000 pathways. To pinpoint the biological features characterizing the DTNs, we performed principal component analysis and computed the Euclidean distance between DTN component scores and feature loading values. DTNs of disease A drugs not contraindicated in B were affiliated with proteins common to A/B networks or uniquely found in the B network, similarly regulated common pathways, and disease-B specific pathways and tissues. DTNs of disease A drugs contraindicated in B were affiliated with common proteins or those uniquely found in the A network, differentially regulated common pathways, and disease A-specific pathways and tissues. Hence, DTN enrichment in pathways, tissues, and PPI networks of comorbid diseases will help identify drugs contraindications in comorbidities.

bioinformatics↗

bioRxiv2021

iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.

cell biology↗

bioRxiv2018

Mesothelioma Interactome with 367 Novel Protein-Protein Interactions

Malignant pleural mesothelioma (MPM) is an aggressive cancer of the thorax with a median survival of one year. We constructed an MPM interactome with over 300 computationally predicted PPIs and over 1300 known PPIs of 62 literature-curated genes whose activity affects MPM. Known PPIs of the 62 MPM associated genes were derived from BioGRID and HPRD databases. Novel PPIs were predicted by applying the HiPPIP algorithm, which computes features of protein pairs such as cellular localization, molecular function, biological process membership, genomic location of the gene, gene expression in microarray experiments, protein domains and tissue membership, and classifies the pairwise features as interacting or non-interacting based on a random forest model. To our satisfaction, the interactome is significantly enriched with genes differentially expressed in MPM tumors compared with normal pleura, and with other thoracic tumors. The interactome is also significantly enriched with genes whose high expression has been correlated with unfavorable prognosis in lung cancer, and with genes differentially expressed on crocidolite exposure. 28 of the interactors of MPM proteins are targets of 147 FDA-approved drugs. By comparing differential expression profiles induced by drug to profiles induced by MPM, potentially repurposable drugs are identified from this drug list. Development of PPIs of disease-specific set of genes is a powerful approach with high translational impact - the interactome is a vehicle to piece together an integrated view on how genes associated with MPM through various high throughput studies are functionally linked, leading to clinically translatable results such as clinical trials with repurposed drugs. The PPIs are made available on a webserver, called Wiki-Pi MPM at http://severus.dbmi.pitt.edu/wiki-MPM with advanced search capabilities.\n\nOne Sentence SummaryMesothelioma Interactome with 367 novel protein-protein interactions may shed light on the mechanisms of cancer genesis and progression

cancer biology↗