Biology subjects

Vashist, N.

Publications and source records attributed to Vashist, N..

4 recordsLinked to original sources

bioRxiv2026

Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression

Bohring-Opitz syndrome (BOS, OMIM#605309) is a rare neurodevelopmental disorder caused by heterozygous and truncating variants in ASXL1 (Additional Sex Combs Like 1), a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB complex with BAP1. Truncating ASXL1 variants are also recurrent somatic drivers in myeloid leukemia, yet the metabolic consequences of these mutations remain undefined. Using patient derived dermal fibroblasts, we show that truncating ASXL1 variants drive a Warburg-like metabolic state characterized by increased glycolytic flux, and accumulation of pyruvate and lactate. Truncated ASXL1 and BAP1 show aberrant co-occupancy at an H3K4me3-marked intronic regulatory element within MPC2 intron 1, with broadened ASXL1 occupancy extending beyond BRD4-defined regulatory boundaries while BRD4 positioning remains unchanged, consistent with aberrant PR-DUB complex spreading beyond its normally constrained chromatin territory. This altered occupancy is accompanied by modest but significant reduction in MPC2 transcript abundance and a disproportionately larger reduction in MPC1 and MPC2 protein levels, indicating that transcriptional dysregulation at this intronic element is amplified at the protein level through post-transcriptional mechanisms including impaired MPC1/MPC2 heterodimer stability. Pharmacologic MPC inhibition recapitulates both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation increases glycolytic flux without reducing MPC abundance, establishing mitochondrial pyruvate restriction as causally upstream of signaling dysregulation. These findings define a previously unrecognized chromatin-to-metabolism axis connecting gain-of-function ASXL1 truncation to mitochondrial pyruvate transport, identifying MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1-mutant myeloid malignancy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/737346v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1d6ee4org.highwire.dtl.DTLVardef@5b6e15org.highwire.dtl.DTLVardef@9849cforg.highwire.dtl.DTLVardef@15ebb5_HPS_FORMAT_FIGEXP M_FIG C_FIG Truncating and heterozygous ASXL1 variants cause a neurodevelopmental syndrome called Bohring-Opitz syndrome. (1) At an epigenetic level, we have shown that Truncating ASXL1 variants drive more open chromatin and aberrant activation of key developmental pathways. (2) Truncating ASXL1 mutations are sufficient to drive Decreased MPC1 and MPC2 protein levels. (3) Decreased MPC1 or MPC2 level or function are sufficient to drive increased glycolysis which is observed in BOS cells. (4) Truncating ASXL1 mutations drive Increased Wnt signaling via MPC depletion. * Increased Wnt signaling (4) is also sufficient to drive increased glycolysis (3), however Increased Wnt signaling does not drive Decreased MPC1 and MPC2 levels (2).

genetics↗

bioRxiv2025

Plasma membrane folate transport in fungi and plants is mediated by members of the oligopeptide transporter (OPT) family

Folates are essential for all organisms. They are acquired either through de novo biosynthesis or from the diet. Yeast, fungi and plants make their own folates and it has not been clear if plasma membrane folate transporters exist in these organisms. Using a synthetic lethal screen in Saccharomyces cerevisiae we observed that deletions in a gene encoding the previously identified glutathione transporter, OPT1, was synthetically sick with a disruption in folate biosynthesis. Uptake experiments confirmed that Opt1p/Hgt1p can transport folinic acid and the naturally abundant methyl tetrahydrofolate. As S. cerevisiae Opt1p was able to transport both folate and glutathione, we used alanine-scanning mutants of the residues in the transmembrane domains of the channel to identify the residues required specifically for the uptake of folates and distinct from those required for glutathione. We further examined the oligopeptide transporter family of other organisms for the presence of folate transporters. In C. albicans, CaOPT1, the orthologue of S. cerevisiae OPT1 efficiently transported folate but not glutathione, while the previously characterized glutathione transporter, CaOPT7 could not transport folate. Aspergillus fumigatus has eight homologues of the oligopeptide transporter family, of which OptB and OptH could transport folates. In the plant Arabidopsis thaliana, the Opt1 homologs AtOpt2, AtOpt4, and AtOpt6 could transport folates. This discovery of folate transporters across fungi and plants fills a critical gap in our understanding of folate metabolism, and can benefit the exploitation of these pathways in pathogenic fungi, and in plants.

genetics↗

bioRxiv2024

Comprehensive benchmark of integrative strategies for analyzing microbiome-metabolome relationships

BackgroundThe exponential growth of high-throughput sequencing technologies was an incredible opportunity for researchers to combine various -omics within computational frameworks. Among these, metagenomics and metabolomics data have gained an increasing interest due to their involvement in many complex diseases. However, currently, no standard seems to emerge for jointly integrating both microbiome and metabolome datasets within statistical models. ResultsThus, in this paper we comprehensively benchmarked nineteen different integrative methods to untangle the complex relationships between microorganisms and metabolites. Methods evaluated in this paper cover most of the researchers goals such as global associations, data summarization, individual associations, and feature selection. Through an extensive and realistic simulation we identified best methods across questions commonly encountered by researchers. We applied the most promising methods in an application to real gut microbial datasets, unraveling complementary biological processes involved between the two omics. We also provided practical guidelines for practitioners tailored to specific scientific questions and data types. ConclusionIn summary, our work paves the way toward establishing research standards when mutually analyzing metagenomics and metabolomics data, building foundations for future methodological developments.

bioinformatics↗

bioRxiv2022

Jagged1 overexpression on T cells induces thymic regulatory T cells leading to thymic involution

We previously described a mouse model, tg66, with a severe defect resulting in diminished thymic size and complete involution by early adulthood. In the current study, we identified overexpression of Jagged1 as a mechanism for the alterations in thymic development in tg66 mice. T cells in the tg66 thymus were skewed towards CD8+ T cells, and within the CD4+ T cell compartment there was an over-representation of Foxp3+ cells. Regulatory Foxp3+ T cells (Tregs) isolated from tg66 mice had increased ST2 and CD103 expression. These Tregs could suppress proliferation to the same extent as conventional Tregs. Corroborating these results, tg66 mice were resistant to experimental induction of neuroinflammation in a common animal model for multiple sclerosis (EAE). Using bone marrow chimeras, we recorded a stark reduction in the number of thymocytes and a corresponding increase in Tregs in the thymus of mice receiving tg66 bone marrow. Conversely, through blocking Jagged1, the number of thymocytes was significantly increased, being concomitantly associated with a drop in the frequency of Tregs. We conclude that Tregs may play a role in thymic involution and could explain early thymic involution or loss as it is observed in diseases of thymic atrophy such as Down syndrome.

immunology↗