STAT1 is essential for hematopoietic stem cell function and maintains a MHC IIhi stem cell subset that resists myeloablation and neoplastic expansion
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ABSTRACT:
PROVIDER: PRJNA750055 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15258100.fastq.gz | Fastqsanger.gz | |||
| SRR15258200.fastq.gz | Fastqsanger.gz | |||
| SRR15258300.fastq.gz | Fastqsanger.gz | |||
| SRR15258400.fastq.gz | Fastqsanger.gz | |||
| SRR15258101.fastq.gz | Fastqsanger.gz |
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Project description:Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but the downstream mechanisms remain unclear and in particular little is known about the role of STAT1 in regulating hematopoietic stem/progenitor cells during homeostasis. Here we show that loss of STAT1 alters the steady state hematopoietic stem and progenitor (HSPC) landscape, impairs HSC function in transplantation assays and delays blood cell regeneration following myeloablation. Under steady state conditions STAT1 was essential for several HSC transcriptional programs including expression of genes involved in virus life cycle, a subset of interferon-stimulated genes, MHC class I genes and genes involved in cell cycle arrest. In addition Stat-1 deficient mice lacked a previously unrecognized quiescent subset of homeostatic HSCs with high levels of MHC II expression (MHC IIhi HSCs). This subset was refractory to 5’-FU induced myeloablation and displayed reduced megakaryocytic potential. Mutant calreticulin, which causes increased megakaryopoiesis in human myeloproliferative neoplasms, gave rise to preferential expansion of MHC IIlo HSCs. These data reveal a STAT1 dependent MHC IIhi quiescent HSC subset and show that STAT1 protects HSCs from proliferative exhaustion.
2022-07-05 | GSE180904 | GEO
Project description:Adult hematopoietic stem cells (HSCs) are predominantly quiescent and can be activated in response to acute stress such as infection or cytotoxic insults. STAT1 is a pivotal mediator of interferon (IFN) signaling and is required for IFN-induced HSC proliferation, but the downstream mechanisms remain unclear and in particular little is known about the role of STAT1 in regulating hematopoietic stem/progenitor cells during homeostasis. Here we show that loss of STAT1 alters the steady state hematopoietic stem and progenitor (HSPC) landscape, impairs HSC function in transplantation assays and delays blood cell regeneration following myeloablation. Under steady state conditions STAT1 was essential for several HSC transcriptional programs including expression of genes involved in virus life cycle, a subset of interferon-stimulated genes, MHC class I genes and genes involved in cell cycle arrest. In addition Stat-1 deficient mice lacked a previously unrecognized quiescent subset of homeostatic HSCs with high levels of MHC II expression (MHC IIhi HSCs). This subset was refractory to 5’-FU induced myeloablation and displayed reduced megakaryocytic potential. Mutant calreticulin, which causes increased megakaryopoiesis in human myeloproliferative neoplasms, gave rise to preferential expansion of MHC IIlo HSCs. These data reveal a STAT1 dependent MHC IIhi quiescent HSC subset and show that STAT1 protects HSCs from proliferative exhaustion.
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Project description:STAT1 is essential for hematopoietic stem cell function and maintains a MHC IIhi stem cell subset that resists myeloablation and neoplastic expansion [LK]
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Project description:LATS1/2 are frequently down-regulated or mutated in endometrial cancer (EC), yet their exact role in endometrial tumor progression remains unclear. In this study, we unexpectedly discovered a new function of LATS1/2 in regulating MHC class I expression in EC. Knockout of LATS1/2 in EC cells led to significant down-regulation of multiple genes within the MHC/HLA Class I family, which weakened the killing effects of PBMCs on tumor cells. Importantly, we found that the regulation of MHC/HLA expression by LATS1/2 does not depend on the classical Hippo pathway but rather involves their direct interaction with STAT1. This interaction causes STAT1 to be phosphorylated at Ser727 or Ser532, promoting its accumulation and movement into the nucleus and enhancing the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, we demonstrated that the kinase-dead mutant LATS1/2 weakens STAT1 phosphorylation at Ser727, supporting our findings. Our results show a positive correlation between the expression levels of LATS1/2, MHC-I, CD8, and p-STAT1 in tissue samples of EC, providing further evidence to support our discoveries. Overall, our findings reveal novel molecular mechanisms underlying tumor immunogenicity deficiency and suggest that LATS1/2 may serve as an immunotherapy biomarker for targeting EC.
2024-06-16 | PXD043500 | Pride
Project description:LATS1/2 is frequently mutated and down-regulated in endometrial cancer (EC), but the contribution of LATS1/2 to endometrial tumor progression remains unclear. Here, we discovered an unexpected role of LATS1/2 in regulating MHC class I expression in EC. We demonstrate that the knockout of LATS1/2 in EC cells resulted in significant down-regulation of multiple genes of MHC/HLA Class I family and leaded to insensitivity to tumor immunotherapy. Furthermore, we found that the regulation of LATS1/2 on MHC/HLA expression does not depend on the classical Hippo pathway but on their direct interaction with STAT1 to phosphorylate STAT1 to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. The kinase-dead mutant LATS1/2 attenuates STAT1 phosphorylation at Ser727. The expressions of LATS1/2, MHC-I, CD8A and p-STAT1（S727）are positive correlation in tissues of EC confirming our findings furtherly. Furthermore, LATS1/2 expression was negatively correlated with tumor stage in EC tissues. These findings reveal novel molecular mechanisms underlying tumor immunogenicity deficiency and elucidate the potential immunotherapy biomarker targeting LATS1/2 in EC.
2024-02-28 | GSE241847 | GEO
Project description:Stat1-null mice (129S6/SvEvTac-Stat1tm1Rds homozygous) uniquely develop estrogen-receptor-positive mammary tumors with incomplete penetrance and long latency. We studied the growth and development of the mammary glands in Stat1-null mice. Stat1-null MGs have faulty branching morphogenesis with abnormal terminal end buds. The Stat1-null MG also fails to sustain growth of 129S6/SvEv wild-type and null epithelium. These abnormalities are partially reversed by added progesterone and prolactin. Transplantation of wild-type bone-marrow into Stat1-null mice does not reverse the mammary gland developmental defects. Media conditioned by Stat1-null epithelium-cleared mammary fat pads does not stimulate epithelial proliferation whereas it is stimulated by conditioned media derived from either wild-type or progesterone and prolactin-treated Stat1-null epithelium-cleared mammary fat pads. Microarrays and multiplex cytokine protein assays showed that the mammary gland of Stat1-null mice had lower levels of growth factors that have been implicated in normal mammary gland growth and development. Transplanted Stat1-null tumors and their isolated cells also grow slower in Stat1-null mammary gland compared to wild-type recipient mammary gland. Stat1-null hosts responded to tumor transplants with granulocytic infiltrates while wild-type hosts show a mononuclear response. These studies demonstrate that growth of normal and neoplastic Stat1-null epithelium primarily depends on the hormonal milieu and factors, such as cytokines, from the mammary stroma. Stat1-null mammary glands were compared to 129SvEv WT mammary glands with respect to development, gene expression profiles, growth factors and histology.
2015-05-01 | E-GEOD-63025 | biostudies-arrayexpress
Project description:The role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 was deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD was found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells stimulated Interferon-γ- dependent epithelial regeneration in co-cultured organoids, and Interferon-γ directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration.
2024-09-09 | GSE276126 | GEO
Project description:Stat1-null mice (129S6/SvEvTac-Stat1tm1Rds homozygous) uniquely develop estrogen-receptor-positive mammary tumors with incomplete penetrance and long latency. We studied the growth and development of the mammary glands in Stat1-null mice. Stat1-null MGs have faulty branching morphogenesis with abnormal terminal end buds. The Stat1-null MG also fails to sustain growth of 129S6/SvEv wild-type and null epithelium. These abnormalities are partially reversed by added progesterone and prolactin. Transplantation of wild-type bone-marrow into Stat1-null mice does not reverse the mammary gland developmental defects. Media conditioned by Stat1-null epithelium-cleared mammary fat pads does not stimulate epithelial proliferation whereas it is stimulated by conditioned media derived from either wild-type or progesterone and prolactin-treated Stat1-null epithelium-cleared mammary fat pads. Microarrays and multiplex cytokine protein assays showed that the mammary gland of Stat1-null mice had lower levels of growth factors that have been implicated in normal mammary gland growth and development. Transplanted Stat1-null tumors and their isolated cells also grow slower in Stat1-null mammary gland compared to wild-type recipient mammary gland. Stat1-null hosts responded to tumor transplants with granulocytic infiltrates while wild-type hosts show a mononuclear response. These studies demonstrate that growth of normal and neoplastic Stat1-null epithelium primarily depends on the hormonal milieu and factors, such as cytokines, from the mammary stroma.
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