Disease-associated astrocyte epigenetic memory promotes CNS pathology [RNA-Seq of p300 KD, ACLY KD and scramble NOD-EAE mice]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252498 | GEO | 2024/03/21
REPOSITORIES: GEO
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Project description:Disease-associated astrocyte epigenetic memory promotes CNS pathology [RNA-Seq of p300 KD, ACLY KD and scramble NOD-EAE mice]
| PRJNA1060769 | ENA
Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.
2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress
Project description:De novo lipogenesis is activated in most cancers. Several lipogenic enzymes are implicated in oncogenesis and represent potential cancer therapeutic targets. RNA interference-mediated depletion of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression in a subset of human cancer cells. Here we demonstrate the molecular basis and potential biomarkers for ACLY-targeting therapy. First, suppression of cancer cell growth by ACLY depletion involves down-regulation of fatty acid elongase ELOVL6 at the transcriptional level. Lipid profiling revealed that ACLY depletion alters fatty acid composition in triglyceride; increased palmitate and decreased longer fatty acids, in accordance with ELOVL6 down-regulation. Second, ACLY depletion increases reactive oxygen species (ROS), whereas addition of antioxidant reduces ROS and attenuates the growth suppression. Third, ACLY depletion or ROS stimulation induce phosphorylation of AMP-activated protein kinase (AMPK), a sensor of energy and lipid metabolism. Analysis of various cancer cell lines revealed that the levels of AMPK phosphorylation (p-AMPK) correlate with the basal ROS levels, and that cancer cells with low basal p-AMPK (i.e., low basal ROS) levels are highly susceptible to ACLY depletion-mediated growth suppression. Finally, in clinical colon cancer tissues, p-AMPK levels are significantly decreased in aggressive tumors and correlate with the levels of 8-hydroxydeoxyguanosine, a hallmark of ROS stimulation. Together, these data suggest that ACLY inhibition suppresses cancer growth via palmitate-mediated lipotoxicity, and p-AMPK could be a predictive biomarker for its therapeutic outcome. Two cell lines are treated with ACLY siRNA. The samples include controls of each cell line.
2014-04-13 | E-GEOD-37243 | biostudies-arrayexpress
Project description:De novo lipogenesis is activated in most cancers. Several lipogenic enzymes are implicated in oncogenesis and represent potential cancer therapeutic targets. RNA interference-mediated depletion of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression in a subset of human cancer cells. Here we demonstrate the molecular basis and potential biomarkers for ACLY-targeting therapy. First, suppression of cancer cell growth by ACLY depletion involves down-regulation of fatty acid elongase ELOVL6 at the transcriptional level. Lipid profiling revealed that ACLY depletion alters fatty acid composition in triglyceride; increased palmitate and decreased longer fatty acids, in accordance with ELOVL6 down-regulation. Second, ACLY depletion increases reactive oxygen species (ROS), whereas addition of antioxidant reduces ROS and attenuates the growth suppression. Third, ACLY depletion or ROS stimulation induce phosphorylation of AMP-activated protein kinase (AMPK), a sensor of energy and lipid metabolism. Analysis of various cancer cell lines revealed that the levels of AMPK phosphorylation (p-AMPK) correlate with the basal ROS levels, and that cancer cells with low basal p-AMPK (i.e., low basal ROS) levels are highly susceptible to ACLY depletion-mediated growth suppression. Finally, in clinical colon cancer tissues, p-AMPK levels are significantly decreased in aggressive tumors and correlate with the levels of 8-hydroxydeoxyguanosine, a hallmark of ROS stimulation. Together, these data suggest that ACLY inhibition suppresses cancer growth via palmitate-mediated lipotoxicity, and p-AMPK could be a predictive biomarker for its therapeutic outcome.
2014-04-13 | GSE37243 | GEO
Project description:ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in non-alcoholic fatty liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol lowering drug bempedoic acid (BPA), which has been shown to improve steatosis in mice. However, the acetyl-CoA synthetase ACSS2 can compensate for ACLY deficiency to support DNL, potentially complicating the targeting of ACLY. We show that hepatic loss of both ACLY and ACSS2 reduces DNL. Nevertheless, even when ACSS2 is suppressed by dietary or genetic means, we find that steatosis is counterintuitively exacerbated with hepatic ACLY deficiency in mice fed a Western diet (WD), linked to reduced expression of PPARa target genes controlling fatty acid oxidation. Conversely, BPA treatment increased fat catabolism and ameliorated WD-mediated lipid accumulation in both WT and liver ACLY knockout mice. Thus, hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation, and BPA improves steatosis independent of ACLY.
2024-08-01 | GSE247358 | GEO
Project description:C57BL6 mice harboring Acly conditional knockout NOTCH1-ΔE-induced leukemias were treated with vehicle (control) or tamoxifen to induce isogenic deletion of Acly.
2025-02-25 | GSE270580 | GEO
Project description:To investigate the regulatory role of ACLY activation in EC functions, we treated HUVEC with ACLY inhibitor BMS-303141 before LPS stimuli. We then performed gene expression profiling analysis using data obtained from RNA-seq of HUVEC lysates.
2023-09-11 | GSE216178 | GEO
Project description:Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1,2,3,4,5,6,7,8 (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR–Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+ memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+ astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.
2025-02-03 | GSE288348 | GEO
Project description:C57BL6 mice harboring Acly conditional knockout NOTCH1-ΔE-induced leukemias were treated with vehicle (control) or tamoxifen to induce isogenic deletion of Acly. Here we report the gene expression profile of leukemic blasts obtained from the spleen from control- or tamoxifen-treated leukemic mice, either in an acute setting or in long-term survival setting
2025-03-15 | GSE227492 | GEO
Project description:C57BL6 mice harboring Acly conditional knockout NOTCH1-ΔE-induced leukemias were treated with vehicle (control) or tamoxifen to induce isogenic deletion of Acly. Here we report the gene expression profile of leukemic blasts obtained from the spleen from control- or tamoxifen-treated leukemic mice, either in an acute setting (72h post-tamoxifen) or in long-term survival setting
2025-02-11 | GSE270579 | GEO