Biology subjects

Vashisht, A.

Publications and source records attributed to Vashisht, A..

3 recordsLinked to original sources

bioRxiv2026

RE-1 silencing transcription factor is reduced in endometriosis and uterine deletion in mice alters progesterone responsiveness

Endometriosis is a steroid-dependent gynecologic disease characterized by progesterone (P4) resistance, subfertility/infertility, and pelvic pain; however, the molecular mechanisms underlying impaired P4 responsiveness in endometriosis tissue are not fully understood. RE-1 silencing transcription factor (REST), a transcriptional regulator implicated in steroid hormone signaling, has emerged as a potential mediator of P4 responsiveness. Here, we investigated the role of REST in endometriosis using human tissues and a uterine-specific Rest conditional knockout mouse model. Immunohistochemical analysis of eutopic endometrium and ectopic lesions from patients with endometriosis revealed significantly reduced nuclear REST expression compared with control endometrium, suggesting loss of functional REST in disease. To assess the physiological consequences of REST deficiency, uterine-specific Rest knockout (Rest d/d) mice were generated. Rest d/d females exhibited progressive subfertility and hyper-estrogenic uterine tissue characteristics that displayed a blunted responsiveness to P4 treatment. Loss of Rest selectively altered expression of P4-responsive genes associated with endometriosis pathology, despite preserved P4 receptor expression. Following induction of experimental endometriosis, female mice that developed endometriotic-like lesions using Rest-deficient donor tissue developed significantly larger lesions that were less responsive to P4 treatment compared to lesions induced using control tissue. Mechanical sensitivity was modestly increased in mice receiving Rest-deficient tissue, whereas vaginal hyperalgesia was unaffected. These findings identify loss of nuclear REST as a feature of endometriosis and support a role of REST in subfertility, lesion progression, and blunted response to P4. REST may represent a novel molecular contributor to altered P4 responsiveness and a potential therapeutic target in endometriosis. Significance StatementEndometriosis is a common disease in women characterized by altered steroid hormone signaling, infertility, and pelvic pain. RE-1 silencing transcription factor (REST) is a candidate regulator of steroid hormone signaling in gynecologic disease but a role in endometriosis pathophysiology remains unexplored. To fill this knowledge gap, our study utilizes human endometrial and endometriotic tissues coupled with a conditional knockout mouse model for uterine Rest deficiency. We show that REST is significantly reduced in eutopic and ectopic endometrial tissue from women with endometriosis and that deletion from mouse uterine tissue recapitulates clinical characteristics in women with endometriosis including progesterone resistance, sub-fertility and pelvic pain. These findings will further guide future research to understand impaired steroid signaling in the pathophysiology of endometriosis.

physiology↗

bioRxiv2025

The interactome of the Bakers' yeast peroxiredoxin Tsa1 implicates it in the redox regulation of intermediary metabolism, glycolysis and zinc homeostasis

Zinc (Zn) is an essential nutrient supporting a range of critical processes. In the yeast Saccharomyces cerevisiae, Zn deficiency induces a transcriptional response mediated by the Zap1 activator, which controls a regulon of [~]80 genes. A subset support zinc homeostasis by promoting zinc uptake and its distribution between compartments, while the remainder mediate an "adaptive response" to enhance fitness of zinc deficient cells. The peroxiredoxin Tsa1 is a Zap1-regulated adaptive factor essential for the growth of Zn deficient cells. Tsa1 can function as an antioxidant peroxidase, protein chaperone, or redox sensor: the latter activity oxidizes associated proteins via a redox relay mechanism. We previously reported that in Zn deficient cells, Tsa1 inhibits pyruvate kinase (Pyk1) to conserve phosphoenolpyruvate for aromatic amino acid synthesis. However, this regulation makes a relatively minor contribution to fitness in low zinc, suggesting that Tsa1 targets other pathways important to adaptation. Consistent with this model, the redox sensor function of Tsa1 was essential for growth of ZnD cells. Using an MBP-tagged version of Tsa1, we identified a redox-sensitive non-covalent interaction with Pyk1, and applied this system to identify multiple novel interacting partners. This interactome implicates Tsa1 in the regulation of critical processes including many Zn-dependent metabolic pathways. Interestingly, Zap1 was a preferred Tsa1 target, as Tsa1 strongly promoted the oxidation of Zap1 activation domain 2, and was essential for full Zap1 activity. Our findings reveal a novel posttranslational response to Zn deficiency, overlain on and interconnected with the Zap1-mediated transcriptional response. Graphical abstractIn ZnD cells, Tsa1 mediates metabolic adaptation by regulation of glycolytic enzymes Pyk1 and Fba1, and supports activity of the Zap1 transcriptional activator via oxidation of the AD2 domain. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/638137v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1ef6858org.highwire.dtl.DTLVardef@ab9682org.highwire.dtl.DTLVardef@12644a3org.highwire.dtl.DTLVardef@1644fe0_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2017

The microprotein Minion controls cell fusion and muscle formation

Although recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, the functional repertoire of this microproteome remains to be determined1. In skeletal muscle, proper development requires fusion of mononuclear progenitors to form multinucleated myotubes, a critical but poorly understood process2,3. Here we report the identification of a small ORF encoding an essential skeletal muscle specific microprotein we term Minion (microprotein inducer of fusion). Myogenic progenitors lacking Minion differentiate normally but fail to form syncytial myotubes, and Minion-deficient mice die perinatally with marked reduction in fused muscle fibers. This fusogenic activity is conserved to the human Minion ortholog, previously annotated as a long noncoding RNA. Loss-of-function studies demonstrate that Minion is the factor providing muscle specific fusogenic function for the transmembrane protein Myomaker4. Remarkably, we demonstrate that co-expression of Minion and Myomaker is sufficient to induce rapid cytoskeletal rearrangement and homogeneous cellular fusion, even in non-muscle cells. These findings establish Minion as a novel microprotein required for muscle development, and define a two-component program for the induction of mammalian cell fusion, enabling both research and translational applications. Importantly, these data also significantly expand the known functions of smORF-encoded microproteins, an under-explored source of proteomic diversity.

cell biology↗