Biology subjects

Dalal, K.

Publications and source records attributed to Dalal, K..

10 recordsLinked to original sources

bioRxiv2026

Effects of Glutamate Delta 1 Receptor (GluD1) Deletion on the Ultrastructural Features of Corticostriatal and Thalamostriatal Synapses in Mice

The glutamate delta 1 receptor (GluD1) represents a unique subtype of ionotropic glutamate receptors that is strongly expressed in the mammalian striatum. Disruptions of the GRID1 gene, which encodes GluD1, have been associated with neuropsychiatric disorders, including schizophrenia and autism spectrum disorder; however, the role of GluD1 in the brain remains poorly understood. Previous studies in mice have demonstrated that the knockout of striatal GluD1 led to fear-conditioning deficits and depressive-like behaviors. Furthermore, these mice exhibited reduced excitatory input to the striatum due to a loss of thalamostriatal innervation, whereas corticostriatal innervation was unaffected. In this study, we examined whether changes in synapse morphology contribute to the observed functional deficits. We found that the ablation of GluD1 does not affect synaptic targeting patterns of corticostriatal and thalamostriatal terminals, using transmission electron microscopy. We further utilized three-dimensional reconstruction to obtain quantitative data on synapse ultrastructure and found no significant changes in corticostriatal and thalamostriatal synaptic components, including the presynaptic terminal volume, postsynaptic density area and morphology, and postsynaptic dendritic spine volume. These findings support a model in which GluD1 regulates input-specific circuit organization and synaptic connectivity rather than the structural morphology of individual synapses.

neuroscience↗

bioRxiv2026

Chemical Proteomic Profiling of the Histaminylation Proteome in Cancer Cells Unveils Uncharted Epigenetic Marks on Core Histones

Histamine is a key signaling molecule in pathophysiology that can exhibit significant regulatory roles in diverse health and disease status. Besides the well-studied noncovalent interactions between histamine and its receptors, protein histaminylation is a recently discovered mechanism of action, through which histamine regulates cellular signaling pathways in a covalent modification manner. Histaminylation is an emerging protein post-translational modification, where an isopeptide bond is formed between the histamine primary amine and {gamma}-carboxyl group of glutamine through a transamidation reaction catalyzed by transglutaminase 2 (TGM2). However, due to the lack of efficient pan-specific antibodies targeting histaminylated glutamine, the histaminylation proteome in cells remains poorly explored. Here, we report the design and development of a novel N{tau}-propargylated histamine (N{tau}-PH) probe as well as its successful application in chemical proteomic profiling of the histaminylation proteome in cancer cells. Notably, new TGM2-catalyzed epigenetic marks on core histones, e.g., H2AX-Q84 and Q104 histaminylation, have been identified from cancer cells and verified. Lastly, the crosstalk between H2AX histaminylation and {gamma}H2AX formation was discovered in this study, suggesting that TGM2-mediated histaminylation plays a critical role in DNA damage responses.

biochemistry↗

bioRxiv2025

Widespread low-affinity motifs enhance chromatin accessibility and regulatory potential in mESCs

Low-affinity transcription factor (TF) motifs are an important element of the cis-regulatory code, yet they are notoriously difficult to map and mechanistically incompletely understood, limiting our ability to interpret non-coding variation in development, evolution, and disease. Here we investigate their role in pioneering and leverage sequence-to-profile models of chromatin accessibility in mouse embryonic stem cells to reliably map and interpret low-affinity motifs across the genome. We find that low-affinity motifs have outsized effects by cooperating with nearby motifs through intra-nucleosomal soft syntax. By modeling nucleosome-mediated cooperativity with a kinetic model, we discover and validate that pioneer cooperativity makes a motif operate at higher pioneering ranges across changing TF concentrations, thereby raising the regulatory potential. These results show that low-affinity motifs can be accurately mapped, shape the properties of developmental enhancers and likely play a widespread role in fine-tuning enhancers during evolution.

genomics↗

bioRxiv2025

TRPV4 Channels Mediate Bladder Cancer Cell Proliferation, Migration and Chemoresistance

Bladder cancer (BLCA) is the second most common urologic cancer in the US and worldwide which mostly affects the aging population. Despite several ongoing clinical trials, treatment paradigms for BLCA have not changed significantly. Here, we investigated the expression of transient receptor potential vanilloid type 4 (TRPV4) in BLCA patients and its role in calcium influx, cell proliferation, and migration using normal human urothelial cells and BLCA cells. Bioinformatic analysis of the UALCAN and cBioPortal databases revealed that TRPV4 expression is significantly higher in human BLCA tissues compared to adjacent normal tissues. Further, the TRPV4 expression was markedly elevated in early-stage BLCA and upregulated in muscle-invasive bladder cancer (MIBC) tissues. TRPV4 is expressed in both normal urothelial (SV-HUC-1) and BLCA (T-24) cells and functional assays demonstrated enhanced TRPV4-mediated calcium influx in T-24 compared to SV-HUC-1 cells. T-24 cells exhibited higher spreading on extracellular matrix (ECM) gels with increasing stiffness (0.2, 8, and 50 kPa) and exhibited migratory phenotype compared to SV-HUC-1 cells. Pharmacological inhibition of TRPV4 significantly reduced proliferation and migration in T-24 cells but had minimal effects on normal cells. Finally, treatment with cisplatin significantly reduced TRPV4 protein levels and TRPV4-mediated calcium influx in chemosensitive UM-UC-3 cells, which remained unchanged in chemoresistant T-24 cells, suggesting a potential role of TRPV4 in chemoresistance. In conclusion, TRPV4 may contribute to bladder cancer progression by regulating cell proliferation and migration and may impart resistance to chemotherapy. Targeting TRPV4 could present a novel therapeutic approach for managing bladder cancer progression and overcoming chemoresistance. Significance StatementThis study identifies TRPV4 as a critical driver of BLCA progression. Elevated TRPV4 gene expression in both early-stage and muscle-invasive bladder cancer (MIBC) tissues is associated with increased calcium signaling, cell proliferation, and migration. Importantly, TRPV4 inhibition selectively reduces BLCA growth and motility. Furthermore, TRPV4 is downregulated by cisplatin in chemo-sensitive but not chemo-resistant BLCA cells, underscoring its key role in bladder cancer chemoresistance. These findings position TRPV4 as a therapeutic target for enhancing BLCA treatment and overcoming drug resistance.

cancer biology↗

bioRxiv2024

Interpretable deep learning reveals the sequence rules of Hippo signaling

The response to signaling pathways is highly context-specific, and identifying the transcription factors and mechanisms that are responsible is very challenging. Using the Hippo pathway in mouse trophoblast stem cells as a model, we show here that this information is encoded in cis-regulatory sequences and can be learned from high-resolution binding data of signaling transcription factors. Using interpretable deep learning, we show that the binding levels of TEAD4 and YAP1 are enhanced in a distance-dependent manner by cell type-specific transcription factors, including TFAP2C. We also discovered that strictly spaced Tead double motifs are widespread highly active canonical response elements that mediate cooperativity by promoting labile TEAD4 protein-protein interactions on DNA. These syntax rules and mechanisms apply genome-wide and allow us to predict how small sequence changes alter the activity of enhancers in vivo. This illustrates the power of interpretable deep learning to decode canonical and cell type-specific sequence rules of signaling pathways. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/580842v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1ee22e9org.highwire.dtl.DTLVardef@1362c82org.highwire.dtl.DTLVardef@1a42512org.highwire.dtl.DTLVardef@17dd619_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2020

A long-range chromatin interaction regulates SATB homeobox 1 gene expression in trophoblast stem cells

SATB homeobox proteins are important regulators of developmental gene expression. Among the stem cell lineages determined during early embryonic development, trophoblast stem (TS) cells exhibit robust SATB expression. Both SATB1 and SATB2 act to maintain trophoblast stem-state. However, the molecular mechanisms that regulate TS-specific Satb expression are not yet known. We identified Satb1 variant 2 as the predominant transcript in trophoblasts. Histone marks, and RNA polymerase II occupancy in TS cells indicated active state of the promoter. A novel cis-regulatory region with active histone marks was identified [~]21kbp upstream of variant 2 promoter. CRISPR/Cas9 mediated disruption of this sequence decreased Satb1 expression in TS cells and chromatin conformation capture confirmed looping of this regulatory region into the promoter. Scanning position weight matrices across the enhancer predicted two ELF5 binding sites in close vicinity of SATB1 sites, which were confirmed by chromatin immunoprecipitation. Knockdown of ELF5 downregulated Satb1 expression in TS cells and overexpression of ELF5 increased the enhancer-reporter activity. Interestingly, ELF5 interacts with SATB1 in TS cells, and the enhancer activity was upregulated following SATB overexpression. Our findings indicate that trophoblast-specific Satb1 expression is regulated by long-range chromatin looping of an enhancer that interacts with ELF5 and SATB proteins.

developmental biology↗

bioRxiv2019

Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbuminpositive Interneurons Attenuates Chronic Stress Adaptions in Male Mice

Hypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that enhanced activity of parvalbumin (PV) expressing GABAergic interneurons (INs) play a role in chronic stress related pathologies. In this study, the role of PFC PV INs in stress related phenotypes were explored using Cre inducible inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). Mice were first tested in the tail suspension test (TST) to determine the effects of PV IN inhibition during acute stress. Following this, the long term impact of PV IN inhibition during chronic variable stress (CVS) was tested in the forced swim test (FST). Acute PV IN inhibition reduced active (struggling) and increased passive coping behaviors (immobility) in the TST. In contrast, inhibition of PV INs during CVS increased active and reduced passive coping behaviors in the FST. Moreover, chronic inhibition of PV INs attenuated CVS-induced changes in Fos expression in the prelimbic cortex, basolateral amygdala and ventrolateral periaqueductal gray and also prevented adrenal hypertrophy and body weight loss associated with chronic stress. Our results suggest differential roles of PV INs to acute vs chronic stress, indicative of distinct biological mechanisms underlying acute vs. chronic stress responses. Our results also indicate a role for PV INs in driving chronic stress adaptation and support literature evidence suggesting cortical GABAergic interneurons as a therapeutic target in stress related diseases.\n\nSIGNIFICANCEStress related diseases are associated with prefrontal hypoactivity, the mechanism of which is currently not known. In this study we showed that by inhibiting prefrontal GABA-ergic Parvalbumin interneurons (PV INs) using DREADDs, we can attenuate some of chronic stress related phenotypes. Additionally, we showed that modulation of PV IN activity during acute vs chronic stress had opposing effects on stress coping strategies, suggesting different underlying mechanisms behind acute vs chronic stress paradigms. Our findings indicate that GABA-ergic PV INs may be involved in driving stress related phenotypes and thereby an important target for treatment of stress-related illnesses. Our data suggest that reducing PV IN activity to promote prefrontal output may be an effective treatment strategy for stress related disorders.

neuroscience↗

bioRxiv2019

Deep learning at base-resolution reveals motif syntax of the cis-regulatory code

The arrangement of transcription factor (TF) binding motifs (syntax) is an important part of the cis-regulatory code, yet remains elusive. We introduce a deep learning model, BPNet, that uses DNA sequence to predict base-resolution ChIP-nexus binding profiles of pluripotency TFs. We develop interpretation tools to learn predictive motif representations and identify soft syntax rules for cooperative TF binding interactions. Strikingly, Nanog preferentially binds with helical periodicity, and TFs often cooperate in a directional manner, which we validate using CRISPR-induced point mutations. Our model represents a powerful general approach to uncover the motifs and syntax of cis-regulatory sequences in genomics data. HighlightsO_LIThe neural network BPNet accurately predicts TF binding data at base-resolution. C_LIO_LIModel interpretation discovers TF motifs and TF interactions dependent on soft syntax. C_LIO_LIMotifs for Nanog and partners are preferentially spaced at [~]10.5 bp periodicity. C_LIO_LIDirectional cooperativity is validated: Sox2 enhances Nanog binding, but not vice versa. C_LI

genomics↗

bioRxiv2019

Epidemiology of Childhood Blindness: a Community based study in Bangladesh

This study has aimed to detect the prevalence and causes of childhood blindness in rural area of Bangladesh. A cross sectional quantitative study design was adopted for this study which carried-out in three unions (sub-districts) of Raiganj upazila of Sirajganj district of Bangladesh. Using a validated tool a screening program was conducted at household level. After initial screening a team of ophthalmologists confirmed the diagnosis by clinical examinations. The prevalence of childhood blindness found was 6.3 per 10,000 children. The rate of uni-ocular blindness was 4.8 per 10,000 children. Congenital problems were the major cause of both uniocular and binocular blindness (UOB: 84% and BB: 92% &). For binocular blindness, whole globe was the responsible site (28.0%, CI: 13.1, 47.7) and cornea was for the uni-ocular blindness (57.8%, CI: 35.3, 78.1). Childhood blindness is a public health problem in Bangladesh. Childhood blindness is common irrespective of gender. Major causes of childhood blindness are congenital.

epidemiology↗

bioRxiv2017

Like Sugar in Milk: Reconstructing the genetic history of the Parsi population

BackgroundThe Parsis, one of the smallest religious community in the world, reside in South Asia. Previous genetic studies on them, although based on low resolution markers, reported both Iranian and Indian ancestries. To understand the population structure and demographic history of this group in more detail, we analyzed Indian and Pakistani Parsi populations using high-resolution autosomal and uniparental (Y-chromosomal and mitochondrial DNA) markers. Additionally, we also assayed 108 mitochondrial DNA markers among 21 ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India.\n\nResultsOur extensive analyses indicated that among present-day populations, the Parsis are genetically closest to Middle Eastern (Iranian and the Caucasus) populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred [~]1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement.\n\nConclusionsWe show that the Parsis are genetically closest to the Neolithic Iranians, followed by present-day Middle Eastern populations rather than those in South Asia and provide evidence of sex-specific admixture from South Asians to the Parsis. Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7thcentury and in agreement with their assimilation into the Indian sub-continents population and cultural milieu \"like sugar in milk\". Moreover, in a wider context our results suggest a major demographic transition in West Asia due to Islamic-conquest.

evolutionary biology↗