Biology subjects

Soota, D.

Publications and source records attributed to Soota, D..

7 recordsLinked to original sources

bioRxiv2026

Enhancers require an active resetting phase after transcriptional activation

Signal-responsive enhancers must activate transcription and then return to a competent but inactive state, yet whether this transition is passive or actively driven has remained unresolved. We define this process as enhancer resetting and identify the androgen receptor (AR) as the factor that executes it as an endogenous response to estrogen signaling, independent of exogenous androgen. As estrogen receptor- (ER) undergoes ligand-induced proteasomal degradation during late-phase signaling, AR progressively accumulates in the nucleus and preferentially occupies highly active, persistent ER enhancers in a transcriptionally silent manner. This late-phase AR binding evicts the pioneer factor FOXA1 from chromatin while preserving baseline accessibility, a handoff mechanism that decouples chromatin openness from active transcription. Conversely, augmenting AR activity by DHT treatment or AR overexpression accelerates FOXA1 eviction, while disrupting AR chromatin binding, either by AR knockdown or a DNA-binding-deficient mutant, prevents it, leaving enhancers in an aberrantly permissive state that drives amplified ER rebinding and transcriptional hyperactivation upon subsequent estrogen stimulation. These findings establish active enhancer resetting as a mechanism safeguarding the fidelity of repeated transcriptional responses. Failure of this mechanism may underlie the transcriptional dysregulation that drives tumor progression and endocrine therapy resistance in ER-positive breast cancer, where estrogen signaling is chronic and cyclic.

molecular biology↗

bioRxiv2025

A Cellular Basis for Heightened Gut Sensitivity in Females

Visceral pain disorders, such as irritable bowel syndrome, exhibit a marked female prevalence. Enhanced signaling between enterochromaffin (EC) cells in the gut epithelium and mucosal sensory nerve fibers likely contributes to this sex bias. Here, we identify a novel estrogen-responsive paracrine pathway in which two enteroendocrine cell types, PYY-expressing L-cells and serotonergic EC cells, communicate to increase gut sensitivity in females. We demonstrate that ER estrogen signaling upregulates the bacterial metabolite SCFA receptor Olfr78 on colonic L-cells, increasing PYY release and their sensitivity to acetate. Elevated PYY acts on neighboring EC cells via NPY1R, thereby enhancing serotonin release and gut pain. We propose that hormonal fluctuations, in conjunction with internal (stress) or environmental (diet) factors, amplify this local estrogen-responsive colonic circuit, resulting in maladaptive gut sensitivity.

physiology↗

bioRxiv2025

Nuclear myosin I mediates genomic clustering of estrogen receptor-α without affecting ligand-induced transcriptional robustness

Ligand-induced transcriptional responses are rapid and robust. Estrogen, one such ligand, exerts its rapid effects through the steroid hormone receptor estrogen receptor-alpha (ER). Upon stimulation, ER binds to clustered enhancers to drive target gene expression. Here, we identify nuclear myosin 1 (NM1/Myo1c) as a positive regulator of ER clustering on enhancers, promoting condensate formation on chromatin. NM1 is enriched on chromatin at the peak of the signaling response, and its depletion leads to a genome-wide reduction in ER occupancy and condensates. Surprisingly, these alterations in chromatin occupancy of ER have minimal impact on estrogen-regulated gene expression, suggesting that transcriptional output remains robust despite disruptions in transcription factor clustering. This study reveals a regulatory axis between Myo1c and ER clustering, offering fresh insights into the intricacies of transcriptional regulation.

molecular 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↗

bioRxiv2023

RNA binding limits the ligand induced transcriptional potential of estrogen receptor-alpha

Transcription factors (TFs) primarily regulate gene expression by binding to DNA through their DNA binding domains (DBD). Additionally, approximately half of these TFs also interact with RNA. However, the role of RNA in enabling TF binding on chromatin and subsequent transcription is poorly understood. Estrogen receptor- (ER) is one such TF that activates genes in response to estrogen stimulation. Here, we report that ER interacts with various types of RNAs in ligand dependent manner via its RNA binding motif in hinge region. RNA binding defects lead to a global loss of ER binding in the genome, particularly at weaker ER motifs. In the absence of RNA binding, the ER exhibits dynamic behavior in the nucleus and unexpectedly, the dynamic binding coincides with robust polymerase loading on ER bound chromatin regions. The higher occupancy of PolII was recapitulated by robust ligand induced transcription of ER-regulated genes. Collectively, our results suggest that RNA interactions strengthen ER binding to chromatin limiting the ligand-dependent transcriptional upregulation of estrogen-induced genes.

molecular biology↗

bioRxiv2020

Discovery of tREP-18, a novel class of tRNA encoded peptide with potent leishmanicidal activity

In the post genomic era, tRNA-derived fragments have emerged as a new class of non-coding gene regulators, those play crucial roles both at the transcriptional and translational levels, in different cellular biogenesis. However, none of the studies has ever asked whether tRNAs can also be translated into peptides with any biological significance. Thus, we present a novel hypothesis which suggested that; design and synthesis of tRNA-derived peptides from prokaryotic genome can be exploited for developing unique chemotherapeutics against neglected tropical diseases, like Visceral leishmaniasis (VL) and its aggressive form known as post kalazar dermal leishmaniasis (PKDL). To achieve this aim, we have used a novel system biology-based strategy, which involved; i) mining of unique tRNAs from E. coli genome and their translation into peptide in silico, ii) designing of theoretical 3D models to evaluate their stability, iii) prediction of their biological activity by screening against anti-parasitic database to filter the lead peptide. Based on this strategy, a unique tRNA-derived peptide (tREP-18) was selected, chemically synthesized, and used in vitro for elucidating its therapeutic significance against L. donovani, a causative agent of VL and PKDL. Our findings demonstrated that, tREP-18 can impose high level toxicity to L. donovani promastigotes, by disrupting the ultrastructural cellular architect, destabilizing the mitochondrial membrane potential ({Delta}{Psi}m), thus leading to drastic reduction in cell viability and proliferation. It also imparted high level of toxicity to BS12 a clinical isolate of PKDL. Conceivably, we for the first time reports a novel tRNA-derived peptide "tREP18" with excellent anti-leishmanial property, which can be further utilized for developing it as antileishmanial drug. One Sentence SummaryHere we report a novel first-in-class tRNA encoded peptide and its super anti-leishmanial characteristics.

synthetic biology↗

bioRxiv2019

Ligand dependent gene regulation by transient ER clustered enhancers

Unliganded nuclear receptors have been implicated in ligand-dependent gene regulation. However, the underlying mechanisms are not fully understood. Here we demonstrate that unliganded ER binds to specific sites in the genome thereby pre-marking them as future functional enhancers. Upon ligand exposure, ER binds to several EREs relatively proximal to the pre-marked, or persistent, ER-bound sites. Interestingly, the persistent sites interact extensively, via chromatin looping, with the proximal transiently bound sites forming ER clustered enhancers in 3D. CRISPR-based deletion of TFF1 persistent site disrupts the formation of its clustered enhancer resulting in the loss of E2-dependent induced expression of TFF1 and its neighboring genes within the same cluster. The clustered enhancers overlap with nuclear ER puncta that coalesce in a ligand-dependent manner. Furthermore, formation of clustered enhancers, as well as puncta, coincide with the active phase of signaling and their later disappearance results in the loss of gene expression even though persistent sites remain bound by ER. Our results establish the role of persistent unliganded ER binding in priming enhancer clusters in 3D that drive transient, but robust, gene expression in a ligand-dependent fashion.

molecular biology↗