Biology subjects

Kundnani, D. L.

Publications and source records attributed to Kundnani, D. L..

7 recordsLinked to original sources

bioRxiv2026

Tumor γδ T-cell abundance is associated with favorable cancer treatment outcomes

Purpose: Clinical response to immune checkpoint blockade (ICB) remains variable. We asked whether immune-cell populations in the tumor microenvironment (TME) are associated with benefit across treatments and tumor types. Experimental Design: We analyzed pretreatment bulk tumor RNA-seq from ICB cohorts and TCGA. Gene-level effects associated with ICB response or TCGA survival were projected onto Human Primary Cell Atlas profiles of 157 cell types. Cox and mixed-effects models accounted for cancer type, cohort, and therapy, as appropriate. After {gamma}{delta} T cells emerged as a leading population, we adjusted their associations for eight CD8 estimators and evaluated them using TRUST4-based TRG/TRD reconstruction and single-cell RNA-seq. Results: {gamma}{delta} T-cell programs were among the signatures consistently associated with ICB response and favorable TCGA survival. Across ICB cohorts, {gamma}{delta} T-cell abundance was associated with response (n=1,356; OR, 1.38; 95% CI, 1.23-1.56) and overall survival (n=1,074; HR, 0.82; 95% CI, 0.76-0.88), with associations persisting after CD8 adjustment. ICB-response-associated cell-type profiles were strongly concordant with chemotherapy response (r=0.92) and moderately concordant with radiation response (r=0.58); targeted and hormone therapy analyses were underpowered. TRUST4 reconstruction and single-cell RNA-seq provided orthogonal support for the {gamma}{delta} signal. Conclusions: Pretreatment {gamma}{delta} T-cell abundance was associated with favorable ICB outcomes and survival across cancers, while related cell-type programs extended to selected non-immunotherapy response settings. Although associative and context dependent, these findings support prospective evaluation of {gamma}{delta} T-cell abundance as a candidate tumor-immune biomarker.

immunology↗

bioRxiv2025

Human ribomes reveal DNA-embedded ribonucleotides as a new type of epigenetic mark

Ribonucleoside monophosphates (rNMPs) are abundant in DNA, but their distribution and function in human nuclear genomes remain unknown. Here, we mapped nearly one million rNMPs per genome across diverse human cell types, defining a nuclear "ribome" with non-random distribution patterns. rNMPs are enriched in C/G-rich sequences, epigenetically marked regions, and telomeres. Conserved ribonucleotide-enriched zones (REZs) overlap with CpG islands and R-loops. rNMP concentration near transcription start sites (TSSs) correlates positively with gene expression. Wild-type cells display a broader gene-expression range than ribonuclease H2A (RNH2A) knockouts, in which loss of rNMP cleavage causes pronounced retention of embedded rG and strand-biased rC near TSSs, both increasing with gene expression. These findings establish DNA-embedded rNMPs as a novel epigenetic mark that modulates human gene expression.

molecular biology↗

bioRxiv2025

Genome-wide ribonucleotide detection in Archaea

Genome integrity is constantly challenged by the incorporation of ribonucleotides (rNMPs) during DNA synthesis. Covalently linked single and several consecutive rNMPs occur in the genome of a number of organisms. They are mainly introduced by DNA polymerases during DNA replication and repair. In general, cells evolved ribonucleases H (RNases H) specialized in the removal of rNMPs from DNA to avoid any detrimental consequences on genome stability. Here, we describe the involvement of types 1 and/or 2 RNases H in processing embedded rNMPs in the genome of two archaeal species Haloferax volcanii and Thermococcus barophilus. Using combined approaches that include alkaline DNA fragmentation, high-throughput ribose-seq DNA sequencing and nucleotide pool quantification, the distribution, identity, level and sequence context of genomic rNMPs are reported and discussed regards to the intracellular balances of dNTPs and rNTPs. Our results confirm the predominant role of type 2 RNase H in the removal of genomic rNMPs. They also reveal rNMP-base compositions, densities, locations, and variations of surrounding bases at rNMP-embedment for each mutant. The cellular roles of the different RNases H in processing rNMPs in the genome of Archaea are discussed.

genomics↗

bioRxiv2023

rNMPID: a database for riboNucleoside Mono-Phosphates In DNA

MotivationRibonucleoside monophosphates (rNMPs) are the most abundant non-standard nucleotides embedded in genomic DNA. If the presence of rNMP in DNA cannot be controlled, it can lead to genome instability. The actual positive functions of rNMPs in DNA remain mainly unknown. Considering the association between rNMPs embedment and various diseases and cancer, the phenomenon of rNMPs embedment in DNA has become a prominent area of research in recent years. ResultsWe introduce the rNMPID database, which is the first database revealing rNMP-embedment characteristics, strand bias, and preferred incorporation patterns in the genomic DNA of samples from bacterial to human cells of different genetic backgrounds. The rNMPID database uses datasets generated by different rNMP-mapping techniques. It provides the researchers with a solid foundation to explore the features of rNMPs embedded in the genomic DNA of multiple sources, and their association with cellular functions, and, in future, disease. It also significantly benefits researchers in the fields of genetics and genomics who aim to integrate their studies with the rNMP-embedment data. AvailabilityrNMPID is freely accessible on the web at https://www.rnmpid.org. Contactxph6113@gmail.com or storici@gatech.edu

bioinformatics↗

bioRxiv2023

Distinct features of ribonucleotides within genomic DNA in Aicardi-Goutieres syndrome (AGS)-ortholog mutants of Saccharomyces cerevisiae

Ribonucleoside monophosphates (rNMPs) are abundantly found within genomic DNA of cells. The embedded rNMPs alter DNA properties and impact genome stability. Mutations in ribonuclease (RNase) H2, a key enzyme for rNMP removal, are associated with the Aicardi-Goutieres syndrome (AGS), a severe neurological disorder. Here, we engineered two AGS-ortholog mutations in Saccharomyces cerevisiae: rnh201-G42S and rnh203-K46W. Using the ribose-seq technique and the Ribose-Map bioinformatics toolkit, we unveiled rNMP abundance, composition, hotspots, and sequence context in these yeast AGS-ortholog mutants. We found higher rNMP incorporation in the nuclear genome of rnh201-G42S than in wild-type and rnh203-K46W-mutant cells, and an elevated rCMP content in both mutants. Moreover, we uncovered unique rNMP patterns in each mutant, highlighting a differential activity of the AGS mutants towards rNMPs embedded on the leading or on the lagging strand of DNA replication. This study guides future research on rNMP characteristics in human genomic samples carrying AGS mutations.

molecular biology↗

bioRxiv2023

Enriched zones of embedded ribonucleotides are associated with DNA replication and coding sequences in the human mitochondrial genome

Abundant ribonucleoside triphosphate (rNTP) incorporation in DNA by DNA polymerases in the form of ribonucleoside monophosphates (rNMPs) is a widespread phenomenon in nature, resulting in DNA structural change and genome instability. The rNMP distribution, characteristics, hotspots, and association with DNA metabolic processes in human mitochondrial DNA (hmtDNA) remain mostly unknown. Here, we utilize the ribose-seq technique to capture embedded rNMPs in mtDNA of six different human cell types with wild-type or mutant ribonuclease (RNase) H2 genotype. The rNMPs are preferentially embedded in the DNA of the light strand in most cell types studied, but not in the liver-tissue cells, in which the rNMPs are dominant on the heavy strand of hmtDNA. We uncover common rNMP hotspots and conserved rNMP-enriched zones across the entire hmtDNA, including in the replication-control region, which may result in the suppression of mtDNA replication. We also show that longer coding sequences have a significantly higher rNMP-embedment frequency per nucleotide. While the composition of the embedded rNMPs varies among the different cell types, by studying the genomic context of embedded rNMPs, we detected common rNMP-embedment patterns in hmtDNA. The genomic contexts of rNMPs found in hmtDNA are mainly distinct from those found in yeast mtDNA, highlighting a unique signature of rNTP incorporation by hmtDNA polymerase {gamma}.

genomics↗

bioRxiv2018

Testing the Gene Expression Classification of the EMT Spectrum

The epithelial-mesenchymal transition (EMT) plays a central role in cancer metastasis and drug resistance - two persistent clinical challenges. Epithelial cells can undergo a partial or full EMT, attaining either a hybrid epithelial/mesenchymal (E/M) or mesenchymal phenotype, respectively. Recent studies have emphasized that hybrid E/M cells may be more aggressive than their mesenchymal counterparts. However, mechanisms driving hybrid E/M phenotypes remain largely elusive. Here, to better characterize the hybrid E/M phenotype(s) and tumor aggressiveness, we integrate two computational methods - (a) RACIPE - to identify the robust gene expression patterns emerging from the dynamics of a given gene regulatory network, and (b) EMT scoring metric - to calculate the probability that a given gene expression profile displays a hybrid E/M phenotype. We apply the EMT scoring metric to RACIPE-generated gene expression data generated from a core EMT regulatory network and classify the gene expression profiles into relevant categories (epithelial, hybrid E/M, mesenchymal). This categorization is broadly consistent with hierarchical clustering readouts of RACIPE-generated gene expression data. We show that the EMT scoring metric can be used to distinguish between samples composed of exclusively hybrid E/M cells and those containing mixtures of epithelial and mesenchymal subpopulations using the RACIPE-generated gene expression data.

systems biology↗