Biology subjects

Bhagat, G.

Publications and source records attributed to Bhagat, G..

4 recordsLinked to original sources

bioRxiv2025

The normal human lymph node cell classification and landscape defined by high-dimensional spatial proteomic.

Lymph nodes (LN) are key secondary lymphoid organs (SLO) for a coordinated immune response. They have been extensively characterized by numerous investigative techniques chiefly as single cell suspensions because they are composed of vagile yet crowded hematolymphoid elements, unfriendly to spatial tissue organization-saving techniques. We comprehensively classify in situ all cells of 19 human LN free of pathology with a 78-marker antibody panel, an hyperplexed cyclic staining method, MILAN, and an analytical bioinformatic pipeline, BRAQUE. A total of 77 cell types were classified, encompassing T, B, innate immune and stromal cells. CD4 and CD8 T-cells were classified into 27 unique subsets by leveraging the expression profiles of TCF7, the presence of co-inhibitory receptors and the spatial distribution. CD5 and TCF7 expression defined novel B-cell types. CD27+ mature B-cells occupied previously unrecognized nodal spaces non-overlapping with the cortex and the plasma-cell rich medullary cords. Type 2 conventional dendritic cells were located in nodular paracortical aggregates. Statistically controlled pairwise neighborhood analysis showed sparse cell-cell interactions, known and new neighbors, established and novel LN landscape niches. A high-dimensional proteomic interrogation of the normal human LN provides spatial allocation of known cell types, novel interactions and the landscape organization.

immunology↗

bioRxiv2025

Enhanced FLI1 accessibility mediates STAG2-mutant leukemogenesis

Chromatin architecture governs transcriptional output and cell identity; however, how its disruption promotes leukemic transformation remains incompletely understood. Here, we show that loss of the cohesin subunit STAG2 creates a hyper-accessible chromatin landscape that amplifies FLI1 activity and extends its binding to ectopic loci. Using multi-omic analyses in human AML samples, cell lines, and mouse models, we identify chromatin-dependent co-occupancy of FLI1 and Menin, accompanied by amplification of Menin occupancy at non-canonical loci beyond its HOXA/MEIS1 targets. Therapeutically, the aberrant expansion of Menin binding drives an altered response towards Revumenib and activates interferon response pathways, creating a therapeutic vulnerability to Menin inhibition. Functionally, STAG2/NPM1c co-mutation drives a stem cell-like immunophenotype and a fully penetrant leukemia in vivo. Collectively, these findings define a model in which cohesin loss rewires transcription factor occupancy to amplify oncogenic chromatin programs and expose context-specific therapeutic dependencies.

cancer biology↗

bioRxiv2022

Structural characterizations of a unusual peptide CORO1C-47aa encoded by circRNA hsa-circ-0000437 associated with endometrial cancer

Circular RNAs, which have covalently closed ends, is a special type of non-coding RNAs. Recent studies reveal that they are associated with various biochemical pathways. One such involvements of circular RNAs is in the onset of different types of cancers. Though the circular RNAs are known as non-coding RNAs, however, some of them are found to possess the capacities to code for proteins. One such circular RNA is hsa-circ-0000437 which is known to code for a short peptide referred to as CORO1C-47aa. The peptide has anti-angiogenic activity and are associated with the prevention of endometrial cancer. However, till date only the amino acid sequence of the peptide is known and no structural details of the peptide are available. Therefore, in this work, our aim was to predict how the peptide would fold and what could be its possible ligand binding sites. We used computational tools to determine the structure of the peptide. The structure was refined by molecular dynamics simulations. The possible binding sites and the binding partners of the peptide were also predicted. From this structure function analysis study, we tried to elucidate the possible mechanism of the involvements of the peptide in the onset of endometrial cancer. This is the first report on the structural characterization of the peptide. This study may therefore be useful in determining the structures of new drug candidates for the treatment of endometrial cancer.

bioinformatics↗

bioRxiv2019

Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs

BackgroundMapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). However, the advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified. ResultsWe performed whole genome methyl-seq on diverse normal cells and tissues and three types of cancers (multiple myeloma, lymphoma, glioblastoma multiforme). After excluding imprinting, the data pinpointed 15,114 high-confidence ASM differentially methylated regions (DMRs), of which 1,842 contained SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies were increased 5 to 9-fold in cancers vs. matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancers showed increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor (TF) binding motifs were similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes tracked with de novo ASM in the cancers. Allele-specific TF binding from ChIP-seq was enriched among ASM loci, but most ASM DMRs lacked such annotations, and some were found in otherwise uninformative "chromatin deserts". ConclusionsASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and TF binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, neuropsychiatric, and neoplastic diseases. Custom genome browser tracks with annotated ASM loci can be viewed at a UCSC browser session hosted by our laboratory (https://bit.ly/tycko-asm)

genomics↗