Zmym2 is essential for methylation of germline genes and active transposons in embryogenesis [RNA-seq]

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. This results in ubiquitous overexpression of LINE1 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.ZMYM2是一种转录抑制因子，其在胚胎发育中的功能迄今尚未得到充分研究。我们发现，Zmym2基因敲除（Zmym2-/-）小鼠会在胚胎发育第10.5天（E10.5）前出现胚胎致死表型。对Zmym2-/-胚胎的分子特征分析揭示了两类显著异常：其一，胚胎无法完成生殖系基因启动子的DNA甲基化与基因沉默，进而导致生殖系基因的广泛上调表达；其二，胚胎无法对小鼠中进化上最年轻、活性最强的长散在核元件（LINE）亚家族进行甲基化并沉默，这会造成LINE1蛋白的普遍过表达，以及转座子-基因融合转录本的异常表达。相互作用与共定位实验数据表明，ZMYM2通过结合非经典多梳蛋白复合物PRC1.6（non-canonical polycomb complex PRC1.6）靶向生殖系基因，而通过TRIM28复合物（TRIM28 complex）靶向转座子。ZMYM2基因敲除的人类胚胎干细胞也表现出年轻LINE元件的异常上调与去甲基化，这表明ZMYM2在活性转座子的沉默调控中存在保守功能。因此，ZMYM2是早期胚胎发生过程中DNA甲基化模式调控的一类重要新调控因子。