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. Interaction and colocalization data indicate that ZMYM2 homes to germline genes via binding to the non-canonical polycomb complex PRC1.6 and to transposons via the TRIM28 complex. 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 embryogenesis.

Ancestral genome reconstruction enhances transposable element annotation by identifying degenerate integrants

“…Among the TFs with the highest proportion of degTE-derived TFBSs, we found the co-repressor of repressor element-1 silencing transcription (CoREST) complex components ZMYM2 and its paralog, ZMYM3. 19 ZMYM2 has been reported to be involved in TE silencing through its interaction with TE DNA, 20 , 21 which may explain its frequent association with degTEs.…”

Ancestral genome reconstruction enhances transposable element annotation by identifying degenerate integrants

“…Among the TFs with the highest proportion of degTE-derived TFBSs, we found the co-repressor of repressor element-1 silencing transcription (CoREST) complex components, ZMYM2 and its paralogue ZMYM3 17 . ZMYM2 has been reported to be involved in TE silencing 18,19 , which may explain their frequent association with degTEs. KRAB domain-containing zinc-finger proteins (KZFPs) are major TFs that recognise TEs, usually binding TE subfamilies of a matching evolutionary age 20,21 .…”

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

“…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.…”

“…[ 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. [ 18,19,21–23 ] Further, most components of PRC1.6 KO have been found to be necessary for embryo survival. [ 18,24–28 ] 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.…”

“…[ 18,19,21–23 ] Further, most components of PRC1.6 KO have been found to be necessary for embryo survival. [ 18,24–28 ] 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.…”