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. 2021 Jun 1;22:167. doi: 10.1186/s13059-021-02375-2

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 4 — Knocking out CBS alters the DNA methylation landscape in normal gastric epithelial cells. a Biochemical position of CBS in the transsulfuration and transmethylation cycles. b CBS protein levels in GES1 CRISPR control and CBS-deficient CRISPR clones. c Cluster dendogram of methylation data indicating branching of GES1 CBS-deficient clones from GES1 parental and CRISPR control cells. d Venn diagram of differential methylation analysis of GES1 CBS-deficient clone 1 and clone 2 compared to parental and CRISPR control cells. e Unsupervised clustering of conserved hypermethylated 9171 CpG sites in GES1 CBS-deficient clones [clone 1, C1; clone 2, C2] across passages. f Breakdown of the GES1 CBS-deficient conserved signature in CpG contexts island, shore, shelf, and open sea; *P < 0.001 according to binomial test; “Annotated” refers to the distribution of CpG probes on the Infinium methylation EPIC array, “Random” refers to the sum of all differentially methylated CpG probes in random pairing of samples. g Comparison of CBS-deficient conserved signatures in GES1 or HFE145 with the “GIM-GC common CIMP” and “GC common CIMP” signatures at CpG islands indicate a larger overlap for hypermethylated (33–38%) events compared to hypomethylation events (16–18%); P < 1 × 10⁻⁴, bootstrapping using 10,000 samples. h Graph showing fold difference of intracellular levels of metabolites in CBS-deficient cells (n = 4–5) compared to controls (n = 5) at 72 h, 1-methyl nicotinamide [MNA] (and related metabolites, nicotinamide mononucleotide [NMN], nicotinamide adenine dinucleotide [NAD], S-adenosyl methionine [SAM], S-adenosyl homocysteine [SAH], and methionine, *P < 0.05 (left panel). Graph showing peak area of extracellular levels of homocysteine, SAM, SAH, and methionine in CBS-deficient cells (n = 5) compared to controls (n = 7) at 24 h, *P < 0.05 (middle panel). Biochemical reaction showing conversion of nicotinamide [NAM] to MNA using a methyl group from SAM, catalyzed by nicotinamide N-methyltransferase [NNMT] (right panel). CBS, cystathionine beta-synthase; CTH, cystathionine gamma-lyase; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; MAT, Methionine adenosyltransferase; MTs, Methyl transferases