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Disease-associated mutations on the STAT5B SH2 domain regulate cholesterol and lipid metabolism in liver [ChIP-seq]

ABSTRACT: 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 generated mice carrying STAT5BY665F (gain-of-function) and STAT5BY665H (loss-of-function) alleles using CRISPR/Cas9-mediated base editing to dissect their impact on metabolic regulation. STAT5BY665F mutants 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 strongly activated lipid, cholesterol, and immune transcriptional programs, while STAT5BY665H failed to induce these pathways. 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. Notably, transcriptional and chromatin remodeling by STAT5B variants displayed sex-dependent differences, with male livers showing more pronounced reprogramming than females. Together, these findings illustrate how alterations in STAT5B activity that alter enhancer activation led to altered metabolic function in liver and adipose tissue.

ORGANISM(S): Mus musculus

PROVIDER: GSE309954 | GEO | 2026/02/12

REPOSITORIES: GEO

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Disease-associated mutations on the STAT5B SH2 domain regulate cholesterol and lipid metabolism in liver [RNA-seq]

Project description: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 generated mice carrying STAT5BY665F (gain-of-function) and STAT5BY665H (loss-of-function) alleles using CRISPR/Cas9-mediated base editing to dissect their impact on metabolic regulation. STAT5BY665F mutants 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 strongly activated lipid, cholesterol, and immune transcriptional programs, while STAT5BY665H failed to induce these pathways. 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. Notably, transcriptional and chromatin remodeling by STAT5B variants displayed sex-dependent differences, with male livers showing more pronounced reprogramming than females. Together, these findings illustrate how alterations in STAT5B activity that alter enhancer activation led to altered metabolic function in liver and adipose tissue.

2026-02-12 | GSE309955 | GEO

Disease-associated mutations on the STAT5B SH2 domain regulate cholesterol and lipid metabolism in liver [RNA-Seq liver]

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Two mutations associated with leukemia that change a single tyrosine residue in the STAT5B SH2 domain have opposite effects on the transcriptional programs controlling hematopoiesis [scRNA-seq]

Project description:Normal hematopoiesis is regulated by various cytokines via the JAK-STAT signaling pathway. Gene deletion studies in mice have demonstrated the crucial role of STAT5B in the proliferation, differentiation, and survival of immune cells. However, the physiological effects of human STAT5B mutations remain poorly understood. Mutations within the SH2 domain of STAT5B have been identified in leukemia patients. In this study, we investigate two specific variants: one that substitutes tyrosine 665 with phenylalanine (STAT5BY665F) and another that substitutes tyrosine 665 with histidine (STAT5BY665H). We introduced these two mutations into the mouse genome and observed distinct and divergent impacts on immune cell function. The STAT5BY665F mutation enhanced STAT5B activity and the establishment of transcriptional enhancers and genetic programs. Conversely, the STAT5BY665H mutation was largely inactive, failing to induce the interleukin-regulated enhancer landscape and gene expression. Both mutations modified immune cell profiles, inducing features characteristic of autoimmune disease. In STAT5BY665F mice, there was an expansion of CD8+ and regulatory CD4+ T cells, whereas STAT5BY665H mice didn’t. Both mutant strains exhibited skin abnormalities; however, only the STAT5BY665F mice developed progressive dermatitis. Introduction of equivalent mutations into STAT5A did not significantly impact hematopoiesis. However, mice carrying mutations in both STAT5A and STAT5B displayed additive effects with highly elevated CD4+ and CD8+ T cells. Our findings demonstrate that different naturally occurring missense mutations identified in leukemia patients, changing a single amino acid within the SH2 domain, can either activate or inactivate STAT5B and thereby impact T cell populations.

2025-02-12 | GSE276312 | GEO

Two mutations associated with leukemia that change a single tyrosine residue in the STAT5B SH2 domain have opposite effects on the transcriptional programs controlling hematopoiesis [RNA-seq]

2025-02-12 | GSE276311 | GEO

Two mutations associated with leukemia that change a single tyrosine residue in the STAT5B SH2 domain have opposite effects on the transcriptional programs controlling hematopoiesis [ChIP-seq]

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Human mutations, altering a single tyrosine in the STAT5B SH2 domain, have opposing impacts on enhancer function and mammary development

Project description:Mammary gland development during pregnancy is controlled by lactogenic hormones via the JAK2-STAT5 pathway. Gene deletion studies in mice have revealed the crucial roles of both STAT5A and STAT5B in establishing the genetic programs necessary for the development of mammary epithelium and successful lactation. Several hundred single nucleotide polymorphisms (SNPs) have been identified in human STAT5B, although their pathophysiological significance remains largely unknown. The SH2 domain is vital for STAT5B activation, and this study focuses on the impact of two specific missense mutations identified in T cell leukemias, the substitution of tyrosine 665 with either phenylalanine (Y665F) or histidine (Y665H). By introducing these human mutations into the mouse genome, we uncovered distinct and opposite functions. Mice harboring the STAT5BY665H mutation failed to develop functional mammary tissue, resulting in lactation failure, while STAT5BY665F mice exhibited accelerated mammary development during pregnancy. Transcriptomic and epigenomic analyses identified STAT5BY665H as Loss-Of-Function (LOF) mutation, impairing enhancer establishment and alveolar differentiation, whereas STAT5BY665F acted as a Gain-Of-Function (GOF) mutation, elevating enhancer formation. Persistent hormonal stimulation through two pregnancies led to the establishment of enhancer structures, gene expression and successful lactation in STAT5BY665H mice. Lastly, we demonstrate that Olah, a gene known to drive life-threatening viral disease in humans, is regulated by STAT5B through a candidate four-partite super-enhancer. In conclusion, our findings underscore the role of human STAT5B variants in modulating mammary gland homeostasis and their critical impact on lactation.

2025-04-09 | GSE270652 | GEO

Human mutations, altering a single tyrosine in the STAT5B SH2 domain, have opposing impacts on enhancer function and mammary development [RNA-seq]

2025-04-09 | GSE270656 | GEO

Adipocyte lipin 1 is positively associated with human metabolic health and regulates mouse systemic metabolism

Project description:Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of nonalcoholic steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health and its loss predisposes mice to nonalcoholic steatohepatitis.

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Gene expression profiling of a mouse model of metabolic syndrome

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