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. 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵6 Joint supervision
↵7 Posthumous
1. More bioinformatic analysis was conducted. Figures 5J, S3B, S5G and much of Figure 6 is new. 2. Text was substantially reorganized. 3. An incorrect accession number in Table S1 was corrected. 4. We removed speculation to the effect that ZMYM2 might be homing to sites of RAR binding. We do observe enrichment of ZMYM2 at sites with DR0 motifs in cluster 5 of Figure 5B, but further analysis (not shown) indicates that ZMYM2 is probably colocalizing with a different, unknown nuclear receptor rather than RAR. Until we know more, we won't even speculate.
