MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption
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ABSTRACT:
PROVIDER: PRJNA313029 | ENA |
REPOSITORIES: ENA
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Project description:The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation.
2017-08-18 | GSE78256 | GEO
Project description:The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation.
2017-08-18 | GSE70015 | GEO
Project description: Not available
| S-EPMC5791885 | biostudies-literature
Project description:MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption
| PRJNA313031 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-08-18 | GSE78257 | GEO
Project description:The coenzyme NAD is consumed by signalling enzymes such as poly-ADP-ribose-polymerases (PARPs) and sirtuins. Understanding the mechanisms of aging-associated NAD decline and how cells cope with decreased NAD concentrations requires model systems reflecting chronic NAD deficiency. To evoke compartment-specific over-consumption of NAD, we have engineered cell lines expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum, and peroxisomes. Additionally, we have engineered cell lines that lack a functional gene for the human mitochondrial transporter SLC25A51 and the NAD biosynthesis enzyme NMNAT3. Isotope-tracer flux measurements and mathematical modelling showed that the lowered NAD concentration limits total NAD consumption kinetically. Moreover, NAD biosynthesis rate and capacity remained unchanged, thereby also precluding an increase of total NAD turnover. The chronic NAD deficiency was surprisingly well tolerated unless the mitochondria were targeted. Oxidative phosphorylation and glycolysis were little affected by NAD over-consumption in the other compartments. Likewise, peroxisomal NAD over-consumption was balanced by mitochondrial NAD decrease to maintain beta-oxidation of very long chain fatty acids in peroxisomes. We propose that subcellular NAD pools are interconnected, with mitochondria acting as a rheostat to facilitate NAD-dependent processes in organelles with excessive consumption.
2024-02-07 | GSE255209 | GEO
Project description:Cellular senescence is a stable cell growth arrest that is implicated in tissue aging and cancer. Senescent cells are characterized by an upregulation of proinflammatory and immunosuppressive cytokines and chemokines, which is termed as senescence-associated secretory phenotype (SASP). NAD+ metabolism plays a critical role in both tissue aging and cancer. However, the role of NAD+ metabolism in regulating the SASP is not well understood. Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the strengths of proinflammatory SASP during senescence. In contrast to downregulation of NAMPT during replicative senescence, NAMPT is upregulated during oncogene-induced senescence. NAMPT selectively regulates proinflammatory, but not immunosuppressive, SASP. NAMPT is regulated by HMGA1 through a distal enhancer element during senescence. HMGA1/NAMPT/NAD+ signaling axis promotes proinflammatory SASP through enhancing glycolysis and mitochondria respiration. Mechanistically, HMGA1/NAMPT promotes proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses p53-mediated inhibition of p38MAPK to enhance NFb activity. SASP regulation by NAD+ metabolism is independent of senescence-associated cell growth arrest. An increase in NAD+ levels is sufficient to convert SASP from low to high levels during replicative senescence. Together, we conclude that NAD+ metabolism governs the strengths of proinflammatory SASP. Given the tumor promoting effects of proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.
2019-03-14 | GSE111841 | GEO
Project description:Transcriptional reprogramming and stimulation of leaf respiration by elevated CO2 concentration is diminished, but not eliminated, under limiting nitrogen supply.
2013-10-15 | GSE50966 | GEO
Project description:Transcriptional reprogramming and stimulation of leaf respiration by elevated CO2 concentration is diminished, but not eliminated, under limiting nitrogen supply. Arabidopsis plants were grown in either ambient (370 ppm) or elevated (750 ppm) CO2 with either ample N supply or limiting N supply. Leaf tissue was harvested from youngest most fully expanded leaves 35 days after plant germination at either midday or midnight.
2013-10-15 | E-GEOD-50966 | biostudies-arrayexpress
Project description:The histone variant macroH2A1.1 plays a role in cancer development and metastasis. To determine the underlying molecular mechanisms, we mapped the genome-wide localization of endogenous macroH2A1.1 in the human breast cancer cell line MDA-MB 231. We demonstrate that macroH2A1.1 specifically binds to active promoters and enhancers in addition to facultative heterochromatin. Selective knock-down of macroH2A1.1 deregulates expression of hundreds of highly active genes. Depending on the chromatin landscape, macroH2A1.1 acts through two distinct molecular mechanisms. The first mitigates excessive transcription by binding over domains including the promoter and the gene body. The second stimulates expression of RNA Polymerase II (Pol II) paused genes, including genes regulating mammary tumor cell migration. In contrast to the first one, macroH2A1.1 specifically associates with the TSS of Pol II paused genes. These processes occur in a predefined local 3D genome organization but do not require rewiring of enhancer-promoter contacts. We thus propose that macroH2A1.1 serves as a transcriptional modulator with a potential role in assisting the conversion of promoter-locked into a productive and elongating Pol II.
2022-03-31 | GSE140022 | GEO