ZMYM2 is essential for methylation of germline genes and active transposons in embryonic development

Abstract

ZMYM2 is a transcriptional repressor whose role in development is largely unexplored. We found that Zmym2−/− mice show embryonic lethality by E10.5. Molecular characterization of Zmym2−/− embryos revealed two distinct defects. First, they fail to undergo DNA methylation and silencing of germline gene promoters, resulting in widespread upregulation of germline genes. Second, they fail to methylate and silence the evolutionarily youngest and most active LINE element subclasses in mice. Zmym2−/− embryos show ubiquitous overexpression of LINE-1 protein as well as aberrant expression of transposon-gene fusion transcripts. ZMYM2 homes to sites of PRC1.6 and TRIM28 complex binding, mediating repression of germline genes and transposons respectively. In the absence of ZMYM2, hypermethylation of histone 3 lysine 4 occurs at target sites, creating a chromatin landscape unfavourable for establishment of DNA methylation. ZMYM2−/− human embryonic stem cells also show aberrant upregulation and demethylation of young LINE elements, indicating a conserved role in repression of active transposons. ZMYM2 is thus an important new factor in DNA methylation patterning in early embryonic development.

A maternal-effectPadi6variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos

“…Interestingly, we found that the more recently evolved LTRs and LINEs that retain transcription had the most highly significant gain of methylation. DNA methylation is required to maintain repression of ERV and LINE transposons in postimplantation embryos ( Dahlet et al 2020 ; Graham-Paquin et al 2023 ), suggesting that hypermethylation may interfere with their timely activation and ZGA in early embryos.…”

Loss of DNA methylation disrupts syncytiotrophoblast development: Proposed consequences of aberrant germline gene activation

“…[20] Similar to de novo DNMTs, a common molecular signature upon loss of PRC1.6 in embryogenesis or embryonic stem cells is the loss of promoter DNA methylation and de-repression of germline genes. [18,19,[21][22][23] Further, most components of PRC1.6 KO have been found to be necessary for embryo survival. [18,[24][25][26][27][28] Although there are varying severities observed across PRC1.6 KO models, many complex components have additional roles and/or functional redundancies that could explain some of this variability.…”

“…[18,19,[21][22][23] Further, most components of PRC1.6 KO have been found to be necessary for embryo survival. [18,[24][25][26][27][28] Although there are varying severities observed across PRC1.6 KO models, many complex components have additional roles and/or functional redundancies that could explain some of this variability.…”

“…The mechanisms underpinning this requirement are still not fully understood, but involve the deposition of repressive marks H2AK119ub and H3K9me3 by RING1B and SETDB1, respectively, and the maintenance of transcriptional repression and exclusion of H3K4me3 by ZMYM2. [18,19] PRC1.6 is targeted to germline promoters by DNA-binding proteins, E2F6 and MGA-MAX heterodimer, that bind CpG-containing motifs enriched within these regions. [20] Similar to de novo DNMTs, a common molecular signature upon loss of PRC1.6 in embryogenesis or embryonic stem cells is the loss of promoter DNA methylation and de-repression of germline genes.…”