Role of histone demethylase LSD1 in hepatic cancer metabolism
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69075 | GEO | 2015/05/21
SECONDARY ACCESSION(S): PRJNA284489
REPOSITORIES: GEO
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Project description:Transcriptome analysis of LSD1-depleted HepG2 cells revealed that LSD1 regulates the expression of glycolytic and mitochondrial metabolism genes. We found that LSD1 is an important regulator of glycolysis and mitochondrial respiration in hepatoma. We depleted LSD1 in HepG2 human hepatoma cells using two different siRNAs, and then carried out an expression microarray experiment.
2015-05-21 | E-GEOD-69075 | biostudies-arrayexpress
Project description:Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand proteins encoded by nuclear genome. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 targets methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), the rate-limiting enzyme for nuclear NAD+ synthesis. Hepatic LSD1 knockout reduces NAD+-dependent Sirt1 and Sirt7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABP and PGC-1, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
2021-02-01 | GSE145089 | GEO
Project description:Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain fully elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. ChIP-seq analysis shows that LSD1 and LSD1-targeted H3K4me2 modulate the expression of mitochondrial genes in liver.
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Project description:We report the identification of LSD1 binding genomic regions in mouse embryonic stem cells (ESC) by high throughput sequencing. By obtaining over 10 million 36 bp reads of sequence from each chromatin immunoprecipitated DNA, we generated genome-wide maps for LSD1 and histone H3 dimethylated on lysine 4 (H3K4me2), the substrate for LSD1 in mouse ESCs. Our results showed an extensive overlap between the LSD1 and H3K4me2 genomic regions and a correlation between the genomic levels of LSD1/H3K4me2 and gene expression, including many highly expressed ESC genes. LSD1 is recruited to the chromatin of cells in the G1/S/G2 phases and is displaced from the chromatin of M phase cells, suggesting that LSD1 or H3K4me2 alternatively occupies LSD1 genomic regions during cell cycle progression. LSD1 knockdown by RNA interference or its displacement from the chromatin by anti-neoplastic agents caused an increase in the levels of a subset of LSD1 target genes. Taken together, these results suggest that cell-cycle dependent association and dissociation of LSD1 with chromatin mediates short-time scale gene expression changes during ES cell cycle progression. Examination of LSD1 and lysine 4 dimethylated histone H3 (H3K4me2) binding genomic regions in embryonic stem cells. Input genomic DNA and DNA immunoprecipitaed with control IgG was included as controls.
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Project description:Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.
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Project description:Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
2024-04-25 | PXD048012 | Pride
Project description:Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
2024-04-25 | PXD048018 | Pride
Project description:Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
2024-04-25 | PXD048041 | Pride
Project description:Biochemical crosstalk between two or more histone modifications is often observed in epigenetic enzyme regulation but its functional significance in cells has been difficult to discern. Prior enzymatic studies have revealed that Lys14 acetylation of histone H3 can inhibit Lys4 demethylation by lysine specific demethylase 1 (LSD1). Here we have engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation. Y391K LSD1 knockin cells show increased repression of a set of genes associated with cellular adhesion. Chromatin profiling revealed that the cis-regulatory regions of these silenced genes display a higher level of H3 Lys14 acetylation than the baseline in unedited, parental cells. Y391K LSD1 knockin cells show diminished H3 mono-methyl Lys4 in the vicinity of these silenced genes, consistent with a role for enhanced LSD1 demethylase activity in these regions. These findings illuminate the functional consequences of disconnecting histone modification crosstalk for a key epigenetic enzyme in gene and chromatin regulation.
2024-05-08 | GSE243231 | GEO