Biology subjects

Pyatkov, M.

Publications and source records attributed to Pyatkov, M..

3 recordsLinked to original sources

bioRxiv2025

Disease-associated mutations in the STAT5B SH2 domain reprogram hepatic cholesterol and lipid metabolism

Growth hormone (GH) signaling through STAT5B is a central regulator of hepatic metabolism, yet the functional consequences of disease-associated STAT5B variants remain poorly understood. Here, we analyzed mice carrying STAT5BY665F (gain-of-function) and STAT5BY665H (loss-of-function) variants and dissect their impact on metabolic regulation. STAT5BY665F mice developed hepatic lipid accumulation, hypercholesterolemia, and enhanced insulin sensitivity, whereas STAT5BY665H mice displayed reduced body weight and impaired insulin responsiveness. Transcriptomic analyses revealed that STAT5BY665F activated lipid, cholesterol, and immune transcriptional programs, while STAT5BY665H failed to induce these pathways. Notably, STAT5BY665F substantially feminized male liver gene expression, inducing 77% of female-biased genes while repressing 51% of male-biased genes, thereby mimicking the persistent STAT5B activation characteristic of female livers. ChIP-seq demonstrated extensive STAT5BY665F enhancer occupancy at metabolic and immune loci, contrasting with the minimal chromatin engagement of STAT5BY665H. Beyond the liver, STAT5BY665F broadly reprogrammed adipose tissue gene expression, activating lipid metabolism and immune regulatory networks, whereas STAT5BY665H exerted more restricted effects. Together, these findings illustrate how alterations in STAT5B activity affect enhancer activation and can lead to changes in metabolic function and hepatic sexual dimorphism.

genomics↗

bioRxiv2025

Single Nucleus MultiOmics Links Novel Transcription Factor Motifs to Murine Hepatic Sex Differences in Chromatin Accessibility and Metabolic Dysfunction-Associated Steatotic Liver Disease

The liver exhibits striking sexual dimorphism in gene expression that impacts drug and lipid metabolism and disease susceptibility, with males showing substantially higher predisposition to metabolic dysfunction-associated steatotic liver disease (MASLD) and its complications including hepatocellular carcinoma. These sex differences are primarily controlled by sexually dimorphic pituitary growth hormone (GH) secretion patterns; however, the underlying transcriptional and epigenetic regulatory networks remain only partially understood. Here, we generated paired single-nucleus chromatin accessibility (snATAC-seq) and gene expression (snRNA-seq) profiles from 46,188 liver nuclei isolated from male, female and continuous GH-infused male mice to comprehensively map the epigenetic basis of hepatic sexual dimorphism. We identified 127,957 accessible chromatin regions genome-wide, including thousands of novel regions enriched specifically in non-parenchymal cells. Sex-biased differentially accessible chromatin regions (DARs) were almost exclusively hepatocyte-localized, and continuous GH infusion feminized their accessibility, demonstrating that plasma GH patterns alone are sufficient to reprogram sex-biased hepatocyte chromatin landscapes. Correlation-based peak-to-gene linkage analysis mapped these DARs to sex-biased gene targets and revealed that regulatory interactions are constrained by topologically associated domain boundaries. Motif enrichment analysis identified both established regulators (STAT5, CUX2, BCL6) and novel transcription factors (TFs) at sex-biased DARs. ATAC-seq footprinting revealed novel TF motifs predicted to be occupied at DARs linked to sex-biased genes implicated in MASLD, providing mechanistic insights into the male bias in fatty liver disease. Further, motif co-occurrence analysis revealed TF clusters likely cooperating to regulate sex-dependent gene expression programs. We also identified stringently cell type-specific regulatory regions with cell type-specific TF motifs that define the regulatory architecture underlying hepatocyte and non-parenchymal cell identities. This comprehensive multiOmic atlas elucidates TF networks controlling sex-dependent liver gene expression and serves as a foundational resource for understanding molecular mechanisms underlying sex disparities in MASLD and other liver diseases.

genomics↗

bioRxiv2022

Interplay between murine sex-biased gene expression and hepatic zonation revealed by single nucleus RNA sequencing

The zonation of liver metabolic processes is well-characterized; however, little is known about the cell type-specificity and zonation of sexually dimorphic gene expression or its growth hormone (GH)-dependent transcriptional regulators. We address these issues using single nucleus RNA sequencing of 32,000 nuclei representing nine major liver cell types. Nuclei were extracted from livers from young adult male and female mice, from male mice infused with GH continuously to mimic the female plasma GH pattern, and from mice treated with TCPOBOP, a xenobiotic agonist ligand of the liver nuclear receptor CAR (Nr1i3). Analysis of these rich transcriptomic datasets revealed: 1) expression of sex-biased genes and their key GH-dependent transcriptional regulators is primarily restricted to hepatocytes and is not a feature of liver non-parenchymal cells; 2) many sex-biased transcripts show sex-dependent zonation within the liver lobule; 3) gene expression is substantially feminized in both periportal and pericentral hepatocytes when male mice are infused with GH continuously; 4) sequencing nuclei increases the sensitivity for detecting thousands of nuclear-enriched lncRNAs and enables determination of their liver cell type-specificity, sex bias and hepatocyte zonation profiles; 5) the periportal to pericentral hepatocyte cell ratio is significantly higher in male than female liver; and 6) TCPOBOP exposure disrupts sex-specific gene expression and hepatocyte zonation within the liver lobule. These findings highlight the complex interconnections between hepatic sexual dimorphism and zonation at the single cell level and reveal how endogenous hormones and foreign chemical exposure can alter these interactions across the liver lobule with large effects on both protein-coding genes and lncRNAs. SynopsisSingle nucleus RNA-seq analysis elucidated the cell type-specificity and zonation of the sex-biased murine liver transcriptome, including thousands of long non-coding RNAs. Xenobiotic exposure induced widespread dysregulation, including both gain and loss of sex-biased gene expression and changes in zonation.

systems biology↗