Biology subjects

Qadiri, M.

Publications and source records attributed to Qadiri, M..

9 recordsLinked to original sources

bioRxiv2026

The Drosophila Secretome

Secreted proteins are synthesized within the cell and actively transported outside, where they contribute to development, physiology, immunity, and cellcell communication. In Drosophila melanogaster, many secreted signaling pathways are evolutionarily conserved, making this species a powerful model for studying human development, cancer, neurobiology, and immune regulation. To assemble the Drosophila secretome, we systematically analyzed all fly protein sequences with computational tools, integrating FlyBase, UniProt and Gene Ontology annotations, and incorporating large-scale proteomics datasets. We identified 4,831 genes encoding putative secreted proteins, assigned confidence scores based on the type and strength of supporting evidence, and generated an online resource (www.flyrnai.org/apps/fly_secretome/) for exploring these data. Comparison with the human secretome shows that 54% of Drosophila secretome genes are conserved in the human genome and of these, 83% are annotated as secreted in human. In addition, comparison with Drosophila single-cell transcriptomic data revealed that secreted proteins are more tissue-specific than other genes. Finally, we demonstrate the utility of this resource by analyzing changes in expression of genes encoding putative secreted proteins during aging based on snRNA-seq datasets from the Aging Fly Cell Atlas.

genetics↗

bioRxiv2026

Rapamycin Mitigates a Sex-biased Convergent Aging Trajectory

Rapamycin extends lifespan across species, yet its cell-type-specific benefits and vulnerabilities remain unclear at whole-organism scale. Here, we present the Rapamycin Fly Cell Atlas (Rapa-FCA), a whole-organism single-nucleus transcriptomic atlas of Drosophila spanning both sexes, multiple ages, 18 cell classes, and 181 cell types. Rapamycin elicited a highly heterogeneous response, with prominent effects in reproductive, digestive, and neuromuscular systems and modest responses in most neuronal populations. Across diverse tissues, we identified a rapamycin-sensitive Convergent Aging Trajectory (CAT), marked by Fkbp12 enrichment and mTORC1-linked metabolic programs, including glycolysis and lipid synthesis. CAT-high nuclei accumulated with age and were preferentially reduced by rapamycin, especially in females, consistent with stronger female lifespan extension. By integrating CAT abundance, aging-clock predictions, and nucleus-ratio changes, we mapped sex- and cell-type-specific geroprotection effects of rapamycin. Together, the Rapa-FCA provides an organism-wide framework for resolving how rapamycin reshapes cellular aging across sex, tissue, and cellular state.

developmental biology↗

bioRxiv2026

Conserved principles of central carbon partitioning in Hippo-Yorkie-driven Drosophila gut tumors

Central carbon metabolism undergoes extensive remodeling in cancers, yet the extent to which the resulting network architectures and operating principles are conserved across species and oncogenic contexts in vivo remains unclear. Here, central carbon metabolism was evaluated in Hippo/Yki-driven Drosophila gut tumors, as Hippo-YAP/TAZ signaling links nutritional cues to metabolic state and contributes to epithelial tumorigenesis and therapy resistance. Using integrated steady-state metabolomics, transcriptomics and [U-13C6]glucose tracing, we defined how Hippo pathway activation reorganizes nutrient utilization and carbon flux in vivo and assessed how the resulting Yki-driven metabolic network aligns with mammalian cancer metabolism. Yki tumors exhibited a Warburg-like state with increased glycolytic throughput and enhanced conversion of glucose-derived carbon to lactate, accompanied by transcriptional upregulation of key glycolytic and lactate-production enzymes. Glucose carbon was also redirected into redox-supporting and anabolic nodes, including activation of the glycerol-3-phosphate shuttle and increased labeling of alanine and serine. Mitochondrial metabolism was reorganized into a non-canonical, segmented TCA network centered on -ketoglutarate, which accumulated and acted as a drain into glutamate/glutamine and 2-hydroxyglutarate rather than supporting complete oxidative turnover. Despite reduced abundance of pentose phosphate intermediates, non-oxidative PPP carbon rearrangements and ribose labeling were maintained, enabling robust glucose contribution to pyrimidine nucleotide pools, including strongly labeled dTTP. Together, these data establish a comprehensive map of Yki-driven central carbon partitioning in vivo and highlight conserved principles of tumor carbon allocation shared across oncogenic contexts and mammalian cancer metabolism.

cancer biology↗

bioRxiv2025

In-situ glial cell-surface proteomics identifies pro-longevity factors in Drosophila

Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining healthy brain function. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins in particular is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied a cell-surface proteomic profiling method to glial cells from intact brains in Drosophila, which enabled us to fully profile cell-surface proteomes in-situ, preserving native cell-cell interactions that would otherwise be omitted using traditional proteomics methods. Applying this platform to young and old flies, we investigated how glial cell-surface proteomes change during aging. We identified candidate genes predicted to be involved in brain aging, including several associated with neural development and synapse wiring molecules not previously thought to be particularly active in glia. Through a functional genetic screen, we identified one surface protein, DIP-{beta}, which is down-regulated in old flies and can increase fly lifespan when overexpressed in adult glial cells. We further performed whole-head single-nucleus RNA-seq and revealed that DIP-{beta} overexpression mainly impacts glial and fat cells. We also found that glial DIP-{beta} overexpression was associated with improved cell-cell communication, which may contribute to the observed lifespan extension. Our study is the first to apply in-situ cell-surface proteomics to glial cells in Drosophila, and to identify DIP-{beta} as a potential glial regulator of brain aging.

neuroscience↗

bioRxiv2025

Renal Coenzyme A (CoA) Production Fuels Stem Cell Proliferation and Tumor Growth

Coenzyme A (CoA), derived from Vitamin B5 (VB5; also called pantothenate), is essential for lipid metabolism, energy production, and cell proliferation. While the intracellular functions of CoA are well-characterized, much less is known about its tissue-specific regulation and systemic physiological roles. Here, using Drosophila melanogaster, we uncover a gut-renal circuit in which dietary VB5 fuels CoA biosynthesis specifically in the Malpighian tubules (MTs, the fly kidney), non-autonomously impacting gut homeostasis. We show that, in the MTs, Myc boosts renal CoA production by directly upregulating the pantothenate kinase Fbl (human PANK1-3 ortholog) and downregulating CG5828, which we characterize as the functional ortholog of the metabolite phosphatase and CoA synthesis suppressor PANK4 (dPANK4). Elevated CoA biosynthesis enhances the mevalonate-isoprenoid pathway activity in the gut, promoting intestinal stem cell proliferation. We further demonstrate that renal CoA production is required for gut tumor growth in a fly model. Consistently, MYC and genes within the CoA-isoprenoid axis display strong association with clinical outcomes in human cancers. Together, our findings establish that Myc-driven CoA metabolism generates an inter-organ signal that couples VB5 availability to stem cell control and tumor growth, and identify the CoA-isoprenoid axis as a targetable metabolic vulnerability in cancer.

genetics↗

bioRxiv2025

Cholinergic Signaling Modulates Intestinal Pathophysiology in a Drosophila Model of Cystic Fibrosis

Cystic fibrosis (CF) is a monogenic genetic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride/bicarbonate channel, which is expressed in certain epithelial cells. Current therapies focus on restoring CFTR function, but many gut-related pathologies persist, highlighting the need for complementary treatments to improve the quality of life of people with CF. In this study, we use Drosophila melanogaster as a model to investigate the gut-specific effects of Cftr loss. We demonstrate that enterocyte specific knockdown of Cftr in flies recapitulates several CF pathologies, including reduced intestinal motility, nutrient malabsorption, and decreased energy stores. Using single-nuclei RNA sequencing (snRNA-seq), we identify significant transcriptional changes in the CF model gut, including the upregulation of acetylcholine esterase (Ace, human AChE), which leads to reduced cholinergic signaling. Cholinergic signaling has been shown to affect CFTR function but this is the first time CFTR loss of function has been shown to alter cholinergic signaling. Functional assays confirm that cholinergic sensitivity is diminished in CF guts. Furthermore, restoring cholinergic signaling via Ace knockdown rescues multiple CF-associated phenotypes. Additionally, we identify the transcription factor Fork head (Fkh), the Drosophila homolog of human FOXA1/FOXA2, which is known to be a positive regulator of Cftr transcription in the intestine, as a positive regulator of Ace expression in CF guts. This study establishes the Drosophila gut as a powerful model to investigate CF pathogenesis, genetic modifiers, and identifies Ace and fkh as genetic modifiers. This work also suggests that enhancing cholinergic signaling may represent a viable therapeutic strategy for gastrointestinal manifestations of CF. Author SummaryCystic fibrosis (CF) is a genetic disease that causes complications in multiple organ systems, including the lungs and gastrointestinal tract. While recent therapies have greatly improved life span and respiratory outcomes in people with CF (pwCF), they continue to report significant gastrointestinal symptoms that impact their quality of life. Therefore, there is a need to better understand the progression of CF in the gut and identify gut specific therapeutic targets to improve patient quality of life. In this study we use Drosophila to model gut specific complications of CF. We show our model recapitulates many CF clinical presentations in the gut demonstrating our model may be clinically relevant. Furthermore, we identify acetylcholine esterase (Ace) as a gene that is increased in our CF model guts that is important for the development of CF pathologies. We additionally, perform a screen to identify a transcriptional regulator of Ace, whose genetic manipulation also regulates CF phenotypes. Our findings not only identify a potential target to alleviate GI symptoms in patients with CF, but also validate the Drosophila gut as a robust model for studying CF pathogenesis, genetic modifiers, and screening therapeutics.

genetics↗

bioRxiv2025

Protein folding stress transcriptionally reprograms muscle metabolism

Cellular stress responses crosstalk with many physiological and metabolic pathways. Muscle cells constantly respond to various endogenous stressors while actively maintaining critical metabolic functions for the tissue and whole animal. The molecular mechanisms of how muscle stress responses transcriptionally reprogram metabolic networks are complex and inadequately understood. Using a multi-omics approach of metabolomics, lipidomics, and single-nuclei RNA-sequencing in Drosophila, we reconstructed the physiological landscape of muscle during chronic activation of endoplasmic reticulum unfolded protein response (UPR), a stress response that ensures the secretion of vital proteins from muscle, known as myokines. By ectopically expressing a constitutively active form of X-box binding protein 1 (Xbp1), a highly conserved transcription factor (TF) and UPR effector, we found that UPR downregulates key metabolic pathways in muscle, including carbohydrate and purine metabolism, while upregulating a robust lipogenic program enriched for phospholipids and several antioxidant metabolic pathways. Using gene regulatory network (GRN) analysis, we linked these metabolic changes to distinct TF regulon activities. The activation of a single TF, Xbp1, increased the activity of other stress response TFs in muscle, including cap-n-collar (cnc/Nrf2), cryptocephal (crc/Atf4), and sterol regulatory element binding protein (SREBP). Simultaneously, we observed decreased activity of TFs, namely Forkhead box O (FoxO), that resulted in downregulated metabolic pathways critical to muscle function, including oxidative phosphorylation and glycolysis. We propose that these GRNs antagonize each other downstream of UPR to reprogram muscle metabolism away from carbohydrates and towards lipogenesis, offering novel insight into how metabolic rewiring can be transcriptionally controlled in response to chronic tissue damage, even to the detriment of organ function.

cell biology↗

bioRxiv2025

TF2TG: an online resource mining the potential gene targets of transcription factors in Drosophila

Sequence-specific transcription factors (TFs) are key regulators of many biological processes, controlling the expression of their target genes through binding to the cis-regulatory regions such as promoters and enhancers. Each TF has unique DNA binding site motifs, and large-scale experiments have been conducted to characterize TF-DNA binding preferences. However, no comprehensive resource currently integrates these datasets for Drosophila. To address this need, we developed TF2TG ("transcription factor to target gene"), a comprehensive resource that combines both in vitro and in vivo datasets to link transcription factors (TFs) to their target genes based on TF-DNA binding preferences along with the protein-protein interaction data, tissue-specific transcriptomic data, and chromatin accessibility data. Although the genome offers numerous potential binding sites for each TF, only a subset is actually bound in vivo, and of these, only a fraction is functionally relevant. For instance, some TFs bind to their specific sites due to synergistic interactions with other factors nearby. This integration provides users with a comprehensive list of potential candidates as well as aids users in ranking candidate genes and determining condition-specific TF binding for studying transcriptional regulation in Drosophila.

bioinformatics↗

bioRxiv2025

The epigenetic factor Zrf1 regulates intestinal stem cell proliferation during midgut regeneration

Stem cells are essential for tissue maintenance and regeneration, balancing self-renewal and differentiation to support homeostasis and repair. Through an RNAi screen in the Drosophila midgut, we identified the epigenetic factor Zrf1 as a critical regulator of intestinal stem cell (ISC) proliferation. Functional analyses reveal that Zrf1 integrates inputs from multiple signaling pathways and interacts with components of the RNA-induced silencing complex (RISC). Zrf1 mutants exhibit elevated expression of transposable elements (TEs) and chromatin disruption, highlighting a broader role in genome stability. Single-nuclei RNA sequencing (snRNA-seq) further demonstrated the influence of Zrf1 on chromatin organization and TE repression, particularly within stem cell progenitors. Our findings suggest that Zrf1 is potentially a key chromatin regulator necessary for maintaining stem cell proliferation and genome integrity, enhancing our understanding of the molecular controls underlying stem cell function and chromatin dynamics.

genetics↗