Biology subjects

Khan, S. U.

Publications and source records attributed to Khan, S. U..

6 recordsLinked to original sources

bioRxiv2026

VEZF1 facilitates pluripotency exit by regulating developmental transcriptional programs and CTCF occupancy

Vascular Endothelial Zinc Finger 1 (VEZF1) is essential for embryonic development, but its role in pluripotency exit remains unclear. Previous work showed that Vezf1-deficient ESCs exhibit impaired differentiation, reduced Dnmt3b expression, and genome-wide hypomethylation. Here, we show that Vezf1-/- ESCs fail to efficiently repress the pluripotency transcriptional program during differentiation, a defect that persists after ectopic Dnmt3b expression. Genome-wide analysis revealed VEZF1 occupancy at regulatory regions of genes involved in several developmental signaling pathways, including MAPK, WNT, and Hippo, as well as at some pluripotency-associated genes. Many VEZF1-bound MAPK genes showed reduced expression in undifferentiated Vezf1-/-ESCs, suggesting that VEZF1 activity contributes to transcriptional competence required for efficient pluripotency exit. VEZF1 loss also led to widespread acquisition of new CTCF sites associated with developmental signaling, a subset of which overlapped VEZF1-bound regulatory regions. CTCF depletion had only limited effects on the expression of the VEZF1-bound MAPK genes examined, indicating that increased CTCF occupancy alone is insufficient to explain their reduced expression in Vezf1-/- ESCs. Together, our findings identify a DNMT3B-independent function of VEZF1 in facilitating the exit from pluripotency and establishing transcriptional competence for differentiation, while revealing a potential role for VEZF1 in regulating CTCF occupancy during developmental state transitions.

developmental biology↗

bioRxiv2025

Integrative in silico and experimental identification of non-covalent UBE2N inhibitors enhancing PARP inhibitor sensitivity

UBE2N, an E2 ubiquitin-conjugating enzyme, has emerged as a compelling therapeutic target in oncology due to its critical roles in DNA damage repair and NF-{kappa}B signalling. While covalent inhibitors have shown preclinical promise, non-covalent inhibitors offer potential advantages in terms of selectivity and reduced off-target effects. However, structural and mechanistic data for non-covalent UBE2N inhibitors remain scarce. To address this gap, we implemented a dual in silico strategy combining structure-based molecular docking and ligand-based 3D pharmacophore modelling. Screening a home library of [~]19,000 compounds targeting both the ubiquitin-binding and cofactor interfaces of UBE2N, we identified 22 candidates suitable for biological evaluation. Among these, two compounds, CERMN-2 and CERMN-16, emerged as promising non-covalent inhibitors. CERMN-16, structurally related to the natural compound Variabine B (identified through 3D pharmacophore screening), significantly reduced SKOV-3 ovarian cancer cell viability and enhanced their sensitivity to the PARP inhibitor Olaparib. CERMN-2, identified through docking, also demonstrated a synergistic effect with Olaparib and showed low toxicity in normal ovarian epithelial cells. Molecular dynamics simulations indicated distinct binding modes for each compound, consistent with their targeted binding sites. Biophysical experiments revealed weak binding of CERMN-16 to UBE2N, whereas CERMN-2 bound UBE2N in two orthogonal assays (Microscale thermophoresis and Nano differential scanning fluorimetry). CERMN-16, and more importantly CERMN-2, therefore represent promising leads for the development of selective, non-natural, non-covalent UBE2N inhibitors. These results provide new insights into UBE2N inhibition and support further investigation of their mechanisms of action and therapeutic potential in combination cancer therapies. HIGHLIGHTSO_LIDual in silico screening (docking and 3D pharmacophore) identified new non-covalent UBE2N inhibitor candidates. C_LIO_LITwo compounds, CERMN-2 and CERMN-16, displayed synergistic activity with Olaparib in ovarian cancer cells. C_LIO_LIMD simulations revealed distinct, site-specific binding modes for both compounds. C_LIO_LIBiophysical assays confirmed UBE2N binding for CERMN-2, identifying it as a promising non-natural, non-covalent lead. C_LI

cancer biology↗

bioRxiv2025

Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production Enhancing Immunotherapy

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the USA due to chemo- and immuno-therapy resistance. We show that focal adhesion kinase (FAK) inhibition with ifebemtinib or tumor genetic FAK knockout (KO) in syngeneic ovarian tumor models stimulated resident large peritoneal macrophages to express CXCL13 chemokine and promoted B cell infiltration. Macrophage GATA6 inactivation prevented CXCL13 expression and enhanced FAK-KO tumor growth. Combining ifebemtinib with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody extended survival with tumor-associated tertiary lymphoid structure formation. Mechanistically, FAK-KO heat-treated conditioned media contained exosomes enriched with omega-3 fatty acids which stimulated macrophage CXCL13 production. Ifebemtinib-treated tumors, FAK-KO exosomes, and purified eicosapentaenoic acid enhanced murine and human HGSOC-associated tumor macrophage reprogramming and CXCL13 expression. Overall, our studies define a tumor to macrophage signaling linkage via omega-3 exosome lipids supporting B cell recruitment, survival, immunotherapy enhancement, and actionable via small molecule FAK inhibition. eTOC BlurbHigh-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation. Bullet pointsO_LIGenetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltration C_LIO_LITumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13 C_LIO_LIFAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structures C_LIO_LIOmega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13 C_LI

cancer biology↗

bioRxiv2021

Nipah virus detection at bat roosts following spillover events in Bangladesh, 2012-2019

Knowledge of the dynamics and genetic diversity of Nipah virus circulating in bats and at the human-animal interface is limited by current sampling efforts, which produce few detections of viral RNA. We report on a series of investigations at bat roosts identified near human Nipah cases in Bangladesh between 2012 and 2019. Pooled bat urine samples were collected from 23 roosts; seven roosts (30%) had at least one sample with Nipah RNA detected from the first visit. In subsequent visits to these seven roosts, RNA was detected in bat urine up to 52 days after the presumed exposure of the human case, although the probability of detection declined rapidly with time. These results suggest that rapidly deployed investigations of Nipah virus shedding from bat roosts near human cases could increase the success of viral sequencing compared to background surveillance and enhance our understanding of Nipah virus ecology and evolution.

ecology↗

bioRxiv2021

Physiological and genetic drivers underpinning canopy development are associated with durum wheat yield in rainfed environments

New durum wheat (Triticum turgidum L. ssp. Durum) cultivars with improved adaptation to variable rainfall environments are required to sustain productivity in the face of climate change. Physiological traits related to canopy development underpin the production of biomass and yield, as they interact with solar radiation and affect the timing of water use throughout the growing season. This study explored the temporal canopy dynamics of durum wheat using a nested-association mapping population evaluated for longitudinal normalized difference vegetation index (NDVI) measurements. Association mapping was performed to identify quantitative trait loci (QTL) for time-point NDVI and spline-smoothed NDVI trajectory traits. Yield effects associated with QTL for canopy development were investigated using data from four rainfed field trials. Four QTL associated with slower canopy closure, improved yield in specific environments, and notably, were not associated with a yield penalty in any environment. This was likely due to optimised timing of water-use and pleiotropic effects on yield component traits, including spike number and spike length. Overall, this study suggests that slower canopy closure is beneficial for durum wheat production in rainfed environments. Selection for traits or loci associated with canopy development may improve yield stability of durum wheat in water limited environments.

genetics↗

bioRxiv2019

Estimation of Genetic Diversity in Genus Mentha Collected From Azad Jammu And Kashmir, Pakistan

Mints are perennial aromatic herbs used both for medicinal and aromatic purposes. Flora of Pakistan has reported six species of genus Mentha. Taxonomy of genus Mentha is more complex and confusing due to inter specific hybridization. The present research is the first documented report from Pakistan for the purpose to dissect Mentha specimens using molecular tools. A total of 17 SCoT and SSR markers used to dissect genetic diversity among 41 Mentha specimens. The results revealed substantial variation among Mentha specimens. The molecular data analyzed through NTSYS and Power marker softwares. Dendrogram constructed on the base of similarity coefficients generated using weighted pair group method of arithmetic means (UPGMA) recorded high level of polymorphism. Polymorphic Information Content (PIC) for molecular markers recorded in the range of 5-8. Mean genetic distance (GD) was estimated in the range from 0.35% to 100%. The minimum and maximum GD recorded in one combination each as P2-P4 and M41-P10. The present study was explored the efficiency of SCoT and SSR markers for evaluating the genetic diversity of medicinal plants. The present research was concluded that both morphological and molecular dendrogram determined considerable level of diversity among Mentha species. Furthermore, specific primers and DNA chloroplast technology could be needed for further molecular analysis to refine the data more up to varietal level.

genetics↗