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. Author manuscript; available in PMC: 2021 Dec 1.
Published in final edited form as: Nat Genet. 2021 May 13;53(6):794–800. doi: 10.1038/s41588-021-00856-5

Fig. 4 |. DNMT3A-mediated CGI hypermethylation is dependent on PRC1.

Fig. 4 |

a, Genome browser representation of ChIP-seq normalized reads for H2AK119ub, DNMT3A1 wild type (WT), DNMT3A1 K299I, DNMT3A1 W330R and RRBS data for CpG methylation (black) in parental and sgRing1a/b mouse MSCs expressing wild-type, K299I or W330R DNMT3A1 at chromosome 17: 29,880–29,895 kb. CGIs (green) and genes from the RefSeq database are annotated at the bottom. b, Boxplots for CpG methylation in parental H2AK119ub peak regions (n = 387,308 CpGs) in parental and sgRing1a/b mouse MSCs expressing DNMT3A1 wild type (gray), K299I (blue) or W330R (orange). The center line represents the median (indicated), the box limits are the 25th and 75th percentiles and the whiskers are the minimum to maximum values. P values were determined by two-sided Wilcoxon rank-sum test. c, Boxplots for CpG methylation at CpG islands in parental H2AK119ub peak regions (n = 278,112 CpGs) in parental and sgRing1a/b mouse MSCs expressing DNMT3A1 wild type (gray), K299I (blue) or W330R (orange). The center line represents the median (indicated), the box limits are the 25th and 75th percentiles and the whiskers are the minimum to maximum values. P values were determined by two-sided Wilcoxon rank-sum test. d, Model depicting changes in DNMT3A genomic localization patterns due to PWWP domain mutations associated with paragangliomas and microcephalic dwarfism. Wild-type DNMT3A is recruited to intergenic regions through PWWP-mediated recognition of H3K36me2. Disease-associated mutations in the PWWP domain abrogate binding to H3K36-methylated nucleosomes, promoting localization of DNMT3A to H2AK119ub-enriched regions that are depleted of H3K36me2, including CpG islands, through UDR-mediated recognition of H2AK119ub. As a result, H2AK119ub-enriched CpG islands become hypermethylated.