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Formaldehyde regulates one-carbon metabolism through S-adenosylmethionine biosynthesis

ABSTRACT: One-carbon metabolism is a universal hub for cellular metabolism and epigenetic regulation.1–3 Here, we report that formaldehyde (FA), a one-carbon unit that organisms produce in substantial quantities through folate metabolism,4 is a regulator of the one-carbon cycle via the biosynthesis of S-adenosyl-L-methionine (SAM), an essential one-carbon building block for synthesis of nucleotides, amino acids, and methylated nucleic acids and proteins.5 Activity-based protein profiling (ABPP) in mouse liver tissue identifies FA-sensitive cysteine sites across the proteome, revealing several one-carbon cycle targets including S-adenosylmethionine synthetase isoform 1 (MAT1A), the terminal enzyme in SAM biosynthesis. Biochemical studies of the formaldehyde-MAT1A interaction establish FA-dependent inhibition of MAT1A activity through a conserved C120 site, as the MAT2A isoform lacking this cysteine is not FA-sensitive. CRISPR knockout-generated HepG2 cell models that predominantly express either MAT1A or MAT2A show that MAT1A-positive cells respond to FA treatment in a dose-dependent manner by decreasing their SAM levels and downstream RNA methylation, whereas the MAT2A-positive cells are not affected by FA. Our findings reveal an unexpected interplay between SAM and FA, two central one-carbon units to influence the overall methylation potential of the cell.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Kevin Bruemmer

LAB HEAD: Christopher J. Chang

PROVIDER: PXD018251 | Pride | 2023-11-02

REPOSITORIES: Pride

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	DTASelect-filter-1.mzid.gz	Mzid
	DTASelect-filter-1.pride.mztab.gz	Mztab
	DTASelect-filter-2.mzid.gz	Mzid
	DTASelect-filter-2.pride.mztab.gz	Mztab
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Genome-wide mapping of MAT2A-associsted regions in bovine blastocysts

Project description:Methionine adenosyltransferase (MAT), that catalyzes the synthesis of S-adenosylmethionine (SAM) from ATP and methionine, is involved in folate-mediated one-carbon metabolism (OCM) that is essential for preimplantation embryos in terms of both short-term periconceptional development and long-term phenotypic programming beyond the periconceptional period. SAM is the universal methyl donor for epigenetic methylation of DNA and histones. In the context of the long-term phenotypic programming by the modulation of OCM during periconceptional period, possible interactions between MAT2A and epigenetic status of specific genes during this period are of particular interest. MAT2A has been proposed to interact with many chromatin-related proteins and be recruited to their specific target genes to constitute gene-regulatory complexes. Thus, in the aim of addressing the possible interaction of MAT2A with specific genomic DNA regions in periconceptional period, we performed a ChIP-seq analysis using MAT2A antibody against bovine blastocysts.

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The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention

Project description:Maintenance of the intracellular levels of the methyl donor S-adenosylmethionine (SAM) is essential for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of MAT2A, which encodes the only SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3´ UTR. Increasing METTL16 occupancy on the MAT2A 3´ UTR is sufficient to induce efficient splicing. We propose that under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which in turn promotes MAT2A splicing. Interestingly, human and S. pombe METTL16 methylate the U6 spliceosomal snRNA at a sequence identical to hp1. These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

2017-05-18 | GSE90914 | GEO

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Project description:Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor of methylation of DNA, RNA and proteins, SAM amount affects gene expression by changing their methylation. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells. However, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation with puromycin labeling in HeLa and Hepa1 cells, we revealed that MAT2A depletion by siRNA or chemical inhibition by cycloleucine reduced protein synthesis in mammalian cells. Overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. MAT2 inhibition did not accompany a reduction in the mTORC1 activity but reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of a fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis. Depletion or inhibition of MAT2 reduced 18S rRNA processing. In addition, by quantitative mass spectrometry, we observed that some translation factors were dynamically methylated in response to the activity of MAT2A or the availability of SAM. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the amount of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced whereas it may support proliferation when SAM is sufficient.

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Project description:One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. Here, we show formaldehyde, a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. Formaldehyde reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). Formaldehyde exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic formaldehyde overload showed a decrease in SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for formaldehyde-dependent SAM depletion, revealing a biochemical feedback cycle between formaldehyde and SAM one-carbon units.

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Project description:Background: Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Methods: Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Results: Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. Conclusions: These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

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TGF-β1/p65/MAT2A: a novel pathway involved in the regulation of intracellular SAM and liver fibrogenesis - Part2

Project description:Hepatic stellate cell (HSC) activation induced by transforming growth factor β (TGF-β1) plays a pivotal role in the fibrogenesis. The complex downstream mediators of TGF-β1 are largely unknown. Here, proteomics analysis and biological validation demonstrated that methionine adenosyltransferase 2A (MAT2A) was significantly upregulated in a CCl4-induced fibrosis mice model and a small molecule NPLC0393, known to block TGF-β1/Smad3 signaling, inhibited its upregulation. In HSC cells, TGF-β1 induced elevation of MAT2A and MAT2β expression as well as reduction of S-adenosylmethionine (SAM) content, which further promoted HSC activation. Functionally, in vivo and in vitro knockdown of MAT2A alleviated CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitated hepatic fibrosis and abolished therapeutic effect of NPLC0393. TGF-β1 induced p65 phosphorylation and NF-κB activation, thereby promoted the transcription of MAT2A and its protein expression. In addition, overexpression of p65 abrogated NPLC0393 mediated inhibition of HSC activation. This study identified a novel pathway TGF-β1/p65/MAT2A that was involved in the regulation of intracellular SAM contents and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis.

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TGF-β1/p65/MAT2A: a novel pathway involved in the regulation of intracellular SAM and liver fibrogenesis - Part1

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