Biology subjects

Yousuf, S.

Publications and source records attributed to Yousuf, S..

6 recordsLinked to original sources

bioRxiv2026

Aberrant expression of stress-related Hsrω-n lncRNA contributes to CGG repeat-mediated toxicity in a Drosophila model of FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disease associated with carriers of premutation (PM) alleles of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Expanded CGG repeats in the PM alleles are sufficient to cause cellular stress and toxicity in animal and cellular models of FXTAS. Here, we show that in a Drosophila transgenic model of FXTAS, expanded CGG repeats result in the overexpression of heat shock RNA omega-nuclear (Hsr{omega}-n), a stress-related long non-coding RNA (lncRNA) that dominantly enhances expanded CGG-induced neurotoxicity, whereas its reduction suppresses CGG-induced neurotoxicity. Furthermore, overexpression of Hsr{omega}-n lncRNA concomitantly resulted in a significant enhancement in its association with Hrb87F, the fly ortholog of one of the previously identified CGG repeat RNA-binding proteins, hnRNP A2/B1, and with the imitation switch (ISWI) protein, a chromatin remodeling factor. We extended the findings of Hsr{omega}-n to show that the mammalian stress-related lncRNAs SatIII and Neat1 are elevated in cells expressing expanded CGG repeats. Together, these findings highlight the critical roles of stress-related lncRNAs in CGG repeat-mediated toxicity and support a model in which the total steady-state levels of stress-related lncRNAs increase in the presence of expanded CGG repeats as part of the normal regulatory response to combat stress. However, the effects of chronic expanded CGG repeat expression in post-mitotic neurons may result in altered distribution and/or sequestration of specific RNA-binding proteins or chromatin remodeling factors associated with stress-related lncRNAs. This could contribute to the altered cellular homeostasis and genomic instability associated with FXTAS. SignificanceIndividuals carrying the FMR1 allele with expanded CGG repeats (55-200) in the 5' untranslated region are predisposed to fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. FXTAS demonstrates incomplete penetrance, suggesting the possible involvement of genetic modifiers in its pathogenesis. We used a transgenic Drosophila FXTAS model to conduct genetic, molecular, and biochemical analyses. Our findings revealed that the expression of expanded CGG repeats aberrantly activates stress-related Hsr{omega}-n lncRNA in Drosophila melanogaster. Overexpression of this lncRNA exacerbates CGG-mediated neurodegeneration, whereas its repression alleviates this effect. Extending these findings to mammalian systems, we observed the upregulation of SATIII and Neat I, functional homologs of Hsr{omega}-n lncRNA, in cells expressing expanded CGG repeats. Collectively, these findings identify stress-related lncRNAs as key mediators of CGG-mediated toxicity and underscore their potential as therapeutic targets for FXTAS.

genetics↗

bioRxiv2025

Identification of novel cis-acting elements, E-box and ISRE, regulating IFNγ-IRF1 axis-mediated NLRC5 expression

NLRC5 and CIITA are the primary transcriptional regulators of MHC class I and MHC class II, respectively, and play essential roles in adaptive immunity. While the regulatory mechanisms of CIITA have been extensively characterized, the transcriptional control of NLRC5 remains incompletely understood. In this study, we identified two novel conserved cis-regulatory elements within the NLRC5 promoter, an E-box and an ISRE. Furthermore, we revealed IRF1 as a novel transcriptional regulator of NLRC5, binding directly to the ISRE within the NLRC5 promoter. Using the newly identified NLRC5 ISRE, we established a screening platform to identify modulators of the IFN{gamma}-IRF1-NLRC5 axis. This system corroborated the inhibitory effects of known viral antagonists and led to the identification of novel SARS-CoV-2 viral factors that suppress IFN{gamma}- mediated IRF1 nuclear translocation, thereby inhibiting the MHC class I pathway. By elucidating the previously unproven molecular mechanism underlying IFN{gamma}-mediated NLRC5 regulation, our study provides critical insights into viral immune evasion strategies and the modulation of antigen presentation. These findings may facilitate the development of MHC class I-targeted therapeutics by modulating the IRF1-NLRC5 axis.

immunology↗

bioRxiv2024

Blind but alive - congenital loss of atoh7 disrupts the visual system of adult zebrafish.

1PurposeVision is the predominant sense in most animal species. Loss of vision can be caused by a multitude of factors resulting in anatomical as well as behavioral changes. In mice and zebrafish, atoh7 mutants are completely blind as they fail to generate retinal ganglion cells during development. In contrast to mice, raising blind zebrafish to adulthood is challenging and this important model is currently missing in the field. Here, we report the phenotype of homozygous mutant adult zebrafish atoh7 mutants that have been raised using adjusted feeding and holding conditions. MethodsThe phenotype of adult mutants was characterized using classical histology and immunohistochemistry as well as optical coherence tomography. In addition, the optokinetic response was characterized. ResultsAdult atoh7 mutants display dark body pigmentation and significantly reduced body length. They fail to form retinal ganglion cells, the resulting nerve fiber layer as well as the optic nerve, and consequently behave completely blindly. In contrast, increased amounts of other retinal neurons and Muller glia are formed. In addition, the optic tectum is anatomically reduced in size, presumably due to the missing retinal input. ConlusionsTaken together, we provide a comprehensive characterization of a completely blind adult zebrafish mutant with focus on retinal and tectal morphology, as a useful model for glaucoma and optic nerve aplasia.

neuroscience↗

bioRxiv2023

Integrated Transcriptomic and Metabolomic Profiling of Sheep Ovarian Tissues Confer their association in Fecundity associated Pathways

BackgroundLow fertility is considered the major constraint in sheep rearing industry depending on several factors like, estrus cycle, ovulation rate and litter size but fecundity of ewe plays a key role in sheep reproduction, influenced by several intrinsic and extrinsic factors. However, genetic improvements of traits associated with reproduction through conventional breeding is a very complex and slow process. In current study, we went through a comprehensive integration of high throughput transcriptomic and metabolomics approaches to understand the role of key regulatory genes and metabolites in fecundity of two different and widely raised sheep breeds (Small Tail Han & Dolang) in different regions of China. ResultUPLC/MS/MS system based metabolomic profiling of ovarian tissue from both breeds results into the identification of 1,423 metabolites, including 542 DEMs (379 upregulated and 163 downregulated). Integration of metabolomics and transcriptomics data identified 48 pathways contributed by 37 genes and 85 metabolites through regulatory network analysis. Functional enrichment analysis showed significantly enriched pathways associated with fecundity including Riboflavin metabolism, xenobiotics, bile acid biosynthesis, and Drug metabolism, which produces hormones for regulation of ovarian function, ovulation, and establishment of pregnancy. Further, analyzed two restrictive constrained plots analyzed via multivariate statistical analysis. In one plot complement component C3 associated with Leukotriene D4, and Uridine 5-diphosphate involved in the processes of Neuroactive legend receptor interaction pathway and in second plot IFNGR1 associated with Progesterone, Fumaric acid, and Cortisone involved in the processes of cancer pathway and any disruptions in hormonal balance may induce cancer, which can affect fertility, menstrual cycles, and overall reproductive health. ConclusionExpression profiling, functional enrichments, co-expression network analysis and integrated transcriptomemetabolome data showed gene-metabolite association in energy metabolism, Inflammation, and drug metabolism, all of which play a role in ovarian physiology and ovarian metabolic disorders. Identification and validation of genes, metabolites, and gene-metabolite interactions will help to elucidate the regulatory mechanisms and pathways underlying sheep fecundity and could be leveraged to improve reproductive traits. Graphical Abstract: Scheme of Study O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/572136v1_ufig1.gif" ALT="Figure 1"> View larger version (119K): org.highwire.dtl.DTLVardef@12a42b7org.highwire.dtl.DTLVardef@182169forg.highwire.dtl.DTLVardef@19b2ed4org.highwire.dtl.DTLVardef@11f9eab_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPAR alpha and PCK1 action in hepatocytes

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents/ameliorates NASH and fibrosis as well as reduces subsequent HCC development without affecting total calorie intake. The timing, length and number of fasting cycles as well as the type of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteomic, transcriptomic and metabolomic analyses identified that PPAR and glucocorticoid receptor (GR)-PCK1 act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis whilst suppressing anabolic lipogenesis. In line, PPAR targets and PCK1 were reduced in human NASH. Additionally, dynamic [18F]FDG-PET analysis in vivo revealed increased [18F]FDG uptake/retention and enhanced gluconeogenesis in the liver upon fasting (in accordance with PPAR and GR-PCK1 activation) when assessed by compartmental modelling. Hepatocyte-specific GR deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Notably, PPAR agonist pemafibrate recapitulated key aspects of hepatic fasting signalling at a molecular level. Therefore, IF or pharmacological mimetics of the PPAR and/or GR-PCK1 axis could be a viable intervention against NASH and subsequent liver cancer. One-Sentence SummaryIntermittent fasting protects against fatty liver disease and liver cancer through concerted PPAR and GR-PCK1 action in hepatocytes.

cancer biology↗

bioRxiv2019

Cold storage reveals distinct metabolic perturbations in processing and non-processing cultivars of potato

Cold-induced sweetening (CIS) causes a great loss to the potato (Solanum tuberosum L.) processing industry wherein selection of potato genotypes using biochemical information through marker-trait associations has found to be advantageous. In the present study, we have performed nuclear magnetic resonance (NMR) spectroscopy-based metabolite profiling on tubers from five potato cultivars (Atlantic, Frito Lay-1533, Kufri Jyoti, Kufri Pukhraj, and PU1) differing in their CIS ability and processing characteristics at harvest and after one month of cold storage at 4{degrees}C. A total of 39 water-soluble metabolites were detected using 1H NMR. Multivariate statistical analysis indicated significant differences in metabolite profiles between processing and non-processing potato cultivars. Further analysis revealed distinct metabolite perturbations as induced by cold storage in both types of cultivars wherein significantly affected metabolites were categorized mainly as sugars, sugar alcohols, amino acids, and organic acids. Significant metabolic perturbations were used to carry out metabolic pathway analysis that in turn tracked 130 genes encoding enzymes (involved directly and/or indirectly) involved in CIS pathway using potato genome sequence survey data. Based on the metabolite perturbations, the possible relevant metabolite biomarkers, significantly affected metabolic pathways, and key candidate genes responsible for the observed metabolite variation were identified. Overall, studies provided new insights in further manipulation of specific metabolites playing a crucial role in determining the cold-induced ability and processing quality of potato cultivars for improved quality traits.\n\nHighlightMetabolomic profiling using 1D 1H-NMR and bioinformatics analysis of potato cultivars for the identification of metabolites and genes controlling biochemical pathways in cold-stored potato tubers

plant biology↗