Biology subjects

Mehta, G.

Publications and source records attributed to Mehta, G..

9 recordsLinked to original sources

bioRxiv2026

Meiotic cohesin paralogs govern cell survival by exhibiting flexibility in partner choice

Erroneous loading of the ring-shaped cohesin complex, especially at centromeres, cause chromosomal segregation defects in both mitosis and meiosis. Mitotic cohesin subunits of this complex, either get replaced or co-exist with their meiotic paralogs during meiosis and also in certain cancers. However, it is unclear whether meiotic paralogs can partner mitotic subunits to form hybrid complexes in somatic cells and if there are any functional consequences on cancer progression. Here, we provide a conceptual framework for the principles of cohesin complex assembly involving non-canonical subunits in proliferating Schizosaccharomyces pombe. We show that chromosome loading, segregation fidelity and cellular proliferation are critically affected by the composition of the available cohesin complexes. We find stark differences in the ability of the meiotic kleisin subunit Rec8 to support robust centromere loading, irrespective of its partner, when compared to the canonical mitotic paralog Rad21. Such variations in cellular growth can be explained by different dwell times of these cohesin complexes on the chromosomes as determined by single-molecule tracking and altered chromatin enrichment. We also discover a unique feature of Rec8, in stabilizing chromatin-bound hypomorphic cohesin mutants that aid in cell survival under restrictive conditions. Overall, we highlight the flexibility of meiotic cohesins in restoring function, albeit at a fitness cost, in the presence of inactivating cohesin mutations. Such imbalances could be exploited by cancers to aid cell survival, but at the expense of increased aneuploidy and genomic instability.

molecular biology↗

bioRxiv2026

Eco-friendly approach to indenodiazepinones from o-formylynones and o-phenylenediamines: Novel pharmacophoric constructs and their anti-bacterial activity

We have conceptualised and executed an efficient, eco-friendly, one-flask, synthetic approach of general applicability to functionally enriched and potentially pharmacophoric tetracyclic indenodiazepinones through a base-mediated reaction cascade between a multifunctional o-formylynones and commercial o-phenylenediamines. The pertinence of this operationally simple, no-waste protocol, embodying many green and sustainable features, has been scoped with 26 variegated examples. This controlled one-pot assembly of novel tetracyclic indenodiazepinones with an unusual placement of an olefin through a reaction cascade involving Schiff base formation, intramolecular aza-Michael addition and a Mannich reaction between o-formylynones and o-phenylenediamines rapidly generates a diverse library poised for exploring their therapeutic potential and medicinal chemistry applications. The newly accessed indenodiazepinones exhibit promising antibacterial activities against many microorganisms and are non-cytotoxic even at higher concentrations. Interestingly, one of the compounds, 3v did not develop resistance in Salmonella Typhimurium (STM) upon repeated exposure to sub-lethal doses up to the 160th cycle, whereas resistance against clinically used antibacterial ciprofloxacin was attained at the 128th cycle. These preliminary findings open avenues towards the development of novel antimicrobial agents with enhanced durability against drug resistance and these efforts are disclosed in this report. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/697289v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1d1d9beorg.highwire.dtl.DTLVardef@2e8560org.highwire.dtl.DTLVardef@36742eorg.highwire.dtl.DTLVardef@105ae7c_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Under Pressure: A unique mechanoresponsive mechanism of body site-specific keratin regulation in palmoplantar epidermis

The palmoplantar epidermis, in adapting to the exceptional mechanical strain it bears during locomotion, is molecularly and histologically distinct from other skin body sites. The mechanisms specifying and maintaining its unique identity remain incompletely defined. Here, we identify the type 1 keratin 9 (KRT9/K9), a protein uniquely expressed in the palmoplantar epidermis, as a key modulator of mechanosensitive YAP1 signaling in response to postnatal mechanical compression. K9 loss-of-function variants, as observed in human KRT9 palmoplantar epidermal differentiation disorder (KRT9-pEDD), result in aberrant YAP1 subcellular partitioning and elevated levels of the stress-induced keratin 16 (KRT16/K16). Krt9 null mice recapitulate these molecular phenotypes as early as postnatal day 3 (P3). We further identify dynamic, YAP1-dependent regulation of Krt16/K16, upstream of Krt9/K9 expression, during early postnatal development in situ and in response to mechanical compression of keratinocytes ex vivo, highlighting the role of mechanical stress in epidermal specification. Mechanistically, K9 interacts with the YAP1 binding protein 14-3-3{sigma} and sequesters YAP1 in the cytoplasm, inhibiting its transcriptional activity; these functions are disrupted by KRT9-pEDD-causing variants in K9. Finally, we demonstrate that genetic or pharmacological inhibition of YAP1 ameliorates palmoplantar keratoderma in Krt9 null mice. These findings reveal a role for mechanical cues in specification and maintenance of palmoplantar skin and suggest new therapeutic interventions for inherited palmoplantar epidermal differentiation disorders (pEDDs).

developmental biology↗

bioRxiv2025

PISA: a versatile interpretation tool for visualizing cis-regulatory rules in genomic data

Sequence-to-function neural networks learn cis-regulatory sequence rules driving many types of genomic data. Interpreting these models to relate the sequence rules to underlying biological processes remains challenging, especially for complex genomic readouts such as MNase-seq, which maps nucleosome occupancy but is confounded by experimental bias. We introduce pairwise influence by sequence attribution (PISA), an interpretation tool that combinatorially decodes which bases contributed to the readout at a specific genomic coordinate. PISA visualizes the effects of transcription factor motifs, detects undiscovered motifs with complex contribution patterns, and reveals experimental biases. By learning the bias for MNase-seq, PISA enables unprecedented nucleosome prediction models, allowing the de novo discovery of nucleosome-positioning motifs and their longrange chromatin effects, as well as the design of sequences with altered nucleosome configurations. These results show that PISA is a versatile tool that expands our ability to train and interpret sequence-to-function neural networks on genomics data and understand the underlying cis-regulatory code.

genomics↗

bioRxiv2025

Receptor tyrosine kinase AXL regulates Golgi organization and function through an adhesion-Arf1 signaling axis in breast and lung cancers

Cell-matrix adhesion regulates membrane trafficking, Golgi organisation and function. Differential Golgi organisation in cancer cells could drive changes in trafficking and processing of cargoes. A simple screen evaluating Golgi organisation identifies breast (MDAMB231 vs MCF7) and lung cancer (A549 vs CaLu1) cell line pairs with differently organised Golgi, regulated differentially by loss of adhesion. In silico analysis of differentially expressed genes in the CCLE database, evaluated for their association with the Golgi in interaction networks and literature, identified AXL as a putative regulator of Golgi in these cancers. AXL prominently localized at the Golgi, undergoes displacement from the Golgi when inhibited by R428 and knocked down using siRNA, causing the Golgi to disorganize. AXL-dependent regulation of Golgi organisation is also dependent on cell-matrix adhesion. AXL binds active Arf1, whose recruitment to the Golgi is vital for its organisation. On loss of adhesion, loss of AXL and active Arf1 from the Golgi, drives its disorganization to affect Golgi-dependent microtubule acetylation and cell surface glycosylation in MDAMB231 and A549 cells respectively. Together, this validates our screen to identify novel regulators of the Golgi, and identifies AXL-Arf1 crosstalk as a vital mediator of its organisation and function in cancer cells.

cell biology↗

bioRxiv2024

Paused Polymerase synergises with transcription factors and RNA to enhance the transcriptional potential of promoters

Regulated pausing of RNA polymerase II (Pol II) is essential for enabling rapid and coordinated transcriptional responses to signalling cues. Pausing also contributes to the formation of nucleosome-free regions with the help of chromatin remodellers. However, if these nucleosome-free regions engage with transcription factors to stimulate the transcription potential of paused promoters is not known. In this study, we demonstrate that ligand-induced estrogen receptor-alpha (ER) binding is stabilized at Pol II-paused sites. This stabilization results from an increased dwell time of ER on chromatin, as revealed by single molecule tracking (SMT) experiments. Notably, short chromatin-associated RNAs generated by the paused Pol II contribute to enhancing ER binding at paused promoters. We also observe that pausing increases histone H3K27 acetylation (H3K27ac) levels, which primes paused promoters for robust transcriptional activation upon release. Collectively, these findings suggest that paused Pol II plays a central role in enhancing transcription factor binding through an RNA-dependent mechanism. This, in turn, results in a more vigorous transcriptional response following pausing release, thus contributing to the fine-tuning of ER-mediated gene regulation.

molecular biology↗

bioRxiv2024

Single-molecule tracking reveals the dynamics of Ipl1 recruitment to the kinetochores and spindles in S. cerevisiae

Aurora kinase B, Ipl1 in Saccharomyces cerevisiae, is the master regulator of cell division required for checkpoint regulation, spindle assembly and disassembly, chromosome segregation, and cytokinesis. Decades of research employed ensemble averaging methods to understand its dynamics and function; however, the dynamic information was lost due to population-based averaging. Here, we use single-molecule imaging and tracking (SMIT) to quantify the recruitment dynamics of Ipl1 at the kinetochores and spindles in live cells. Our data suggest that Ipl1 is recruited to these locations with different dynamics. We have demonstrated how the recruitment dynamics of Ipl1 at the kinetochores during metaphase changes in the presence and absence of tension across the kinetochore, in the absence of protein phosphatase 1 (Glc7), and the absence of its known recruiters (Ctf19 and Bub1). The SMIT of other chromosome passenger complex members suggests its hierarchical assembly at the kinetochore. Hence, SMIT provides a dynamic view of the Ipl1 trafficking at the kinetochores and spindles.

cell biology↗

bioRxiv2023

Impact of Yaq-001, a non-absorbable, engineered carbon bead of controlled porosity in rodent models of cirrhosis and acute on chronic liver failure

ObjectiveTranslocation of gut bacterial lipopolysaccharide (LPS) is associated with complications of cirrhosis. Current strategies to target bacterial translocation are limited to antibiotics with risk of resistance. This study aims to explore therapeutic potential of a non-absorbable, engineered carbon bead, Yaq-001 in cirrhosis and acute-on-chronic liver failure (ACLF) models. DesignThe performance of Yaq-001 was evaluated in in vitro studies. Two-rodent models of cirrhosis (4-week, bile duct ligation (BDL): Sham (n=36); Sham-Yaq-001 (n=30); BDL (n=37); BDL-Yaq-001 (n=44)) and ACLF (BDL-LPS: Sham-LPS (n=9); Sham-LPS-Yaq-001 (n=10); BDL-LPS (n=16); BDL-LPS-Yaq-001(n=12)). The treated-groups received Yaq-001 for 2-weeks. Samples were collected for assessment of organ and immune function, transcriptomics, microbiome composition and metabolomics. ResultsIn vitro, Yaq-001 exhibited rapid adsorption kinetics for endotoxin and bile acids without exerting an antibiotic effect. In vivo, Yaq-001 produced significant improvement in ALT, ammonia, liver cell death, portal pressure, markers of systemic inflammation and renal function in BDL animals. Yaq-001-treated ACLF animals had significantly better survival, ALT, portal pressure, brain water and creatinine. Ex-vivo LPS-induced reactive oxygen species production in portal venous monocytes and Kupffer cell populations was diminished with Yaq-001 treatment. Transcriptome analysis demonstrated a significant modulation of inflammation, cell death and senescence pathways in the liver, kidneys, brain and colon of Yaq-001-treated BDL rats. Yaq-001 impacted positively on the microbiome composition with significant modulation of Family Porphyromonadaceae and Genus Barnesiella. Urinary 1HNMR analysis suggested a shift in metabolomic signature in Yaq-001-treated BDL rats. ConclusionsThis study provides strong pre-clinical rationale for developing Yaq-001 for treatment of patients with cirrhosis. Significance of this studyO_ST_ABSWhat is already known on this topic?C_ST_ABSCurrent strategies to target bacterial translocation in cirrhosis are limited to antibiotics with risk of resistance. Yaq-001 is an insoluble, non-absorbable, non-antibiotic, engineered carbon bead of tailored porosities, which works as an adsorbent in the gut and is completely excreted after oral administration. What this study adds?O_LIYaq-001 rapidly adsorbs endotoxin, ammonia and bile acids without influencing bacterial growth kinetics in vitro. C_LIO_LIYaq-001 reduces mortality of ACLF animals and impacts positively on markers of gut permeability, liver injury, portal pressure, brain and kidneys in rodent models of cirrhosis and ACLF. C_LIO_LIYaq-001 administration was associated with positive impact on the composition of the gut microbiota, reduction in severity of endotoxemia and ammonia, which significantly reduced the severity of inflammation, cell death, signaling pathways and LPS sensitivity. C_LI How this study might affect research, practice or policy?The data provide the pre-clinical rationale to proceed to clinical trials in patients with cirrhosis aiming to prevent the occurrence of complications.

animal behavior and cognition↗

bioRxiv2019

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

RationaleHigh-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.\n\nMethodsMEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.\n\nResultsMEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133+ fraction and increased expression of stemness-associated genes. Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions.\n\nConclusionsMEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumor growth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

cancer biology↗