Crosstalk with DNAme and H3K9me3. (A) The short isoform of DNMT3A (DNMT3A2) is expressed in ESCs and it is targeted to H3K36me2-marked intergenic regions via its PWWP domain. The long isoform (DNMT3A1), which is the predominant form in specific adult cell types, including neurons but not glia, additionally processes a UIM domain that targets it to H2AK119ub-marked flanking regions of bivalent promoters. Loss-of-function of this domain results in hypomethylation of these promoters concomitant with both up- and downregulation of gene expression (Gu et al., 2022). (B) During ESC-to-EpiLC differentiation, some non-CGI PRC2 targets acquire de novo DNAme. DNAme evicts PRC2 at some sites (right) but not at the others (left), providing an explanation for the dual role of DNAme in transcription regulation (Albert et al., 2023, Preprint). (C) Germline genes are repressed by default and are only activated during germ cell development. Before implantation, this repression depends on ncPRC1.6 and SETDB1. ncPRC1.6 is recruited by sequence-specific recognition of E-box and E2F motifs by its MGA/MAX and E2F6 subunits, respectively, and SETDB1 recruitment at least partially depends on ncPRC1.6. ncPRC1.6 and SETDB1 are required for efficient recruitment of DNMT3A/B, which establishes post-implantation de novo DNA methylation that contributes to long-term repression of germ-line genes (Mochizuki et al., 2021). (D) While the maternal PCH is consistently marked by H3K9me3 that represses the transcription of the underlying major satellite sequences, the patPCH is initially devoid of H3K9me3 and instead repressed by cPRC1 upon fertilization. The gradual accumulation of H3K9me3 deposited initially by SUV39H2 and then by SUV39H1 at patPCH evicts cPRC1, resulting in a transition from cPRC1-dependent to H3K9me3-dependent repression of pericentromeric major satellites. However, the initial H3K9me3 deposited by SUV39H2 appears to be compatible with gene expression and might be required for the transient activation of some two-cell or four-cell stage-specific genes (Burton et al., 2020).
Figure 4.

Crosstalk with DNAme and H3K9me3. (A) The short isoform of DNMT3A (DNMT3A2) is expressed in ESCs and it is targeted to H3K36me2-marked intergenic regions via its PWWP domain. The long isoform (DNMT3A1), which is the predominant form in specific adult cell types, including neurons but not glia, additionally processes a UIM domain that targets it to H2AK119ub-marked flanking regions of bivalent promoters. Loss-of-function of this domain results in hypomethylation of these promoters concomitant with both up- and downregulation of gene expression (Gu et al., 2022). (B) During ESC-to-EpiLC differentiation, some non-CGI PRC2 targets acquire de novo DNAme. DNAme evicts PRC2 at some sites (right) but not at the others (left), providing an explanation for the dual role of DNAme in transcription regulation (Albert et al., 2023, Preprint). (C) Germline genes are repressed by default and are only activated during germ cell development. Before implantation, this repression depends on ncPRC1.6 and SETDB1. ncPRC1.6 is recruited by sequence-specific recognition of E-box and E2F motifs by its MGA/MAX and E2F6 subunits, respectively, and SETDB1 recruitment at least partially depends on ncPRC1.6. ncPRC1.6 and SETDB1 are required for efficient recruitment of DNMT3A/B, which establishes post-implantation de novo DNA methylation that contributes to long-term repression of germ-line genes (Mochizuki et al., 2021). (D) While the maternal PCH is consistently marked by H3K9me3 that represses the transcription of the underlying major satellite sequences, the patPCH is initially devoid of H3K9me3 and instead repressed by cPRC1 upon fertilization. The gradual accumulation of H3K9me3 deposited initially by SUV39H2 and then by SUV39H1 at patPCH evicts cPRC1, resulting in a transition from cPRC1-dependent to H3K9me3-dependent repression of pericentromeric major satellites. However, the initial H3K9me3 deposited by SUV39H2 appears to be compatible with gene expression and might be required for the transient activation of some two-cell or four-cell stage-specific genes (Burton et al., 2020).

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