Department of Obstetrics, Gynecology and Reproductive Science; Center for Reproductive Sciences; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
Development. 2019 Feb 1;146(12):dev171157. doi: 10.1242/dev.171157.
Epigenetic resetting in germ cells during development de-represses transposable elements (TEs). piRNAs protect fetal germ cells by targeted mRNA destruction and deposition of repressive epigenetic marks. Here, we provide the first evidence for an active piRNA pathway and TE repression in germ cells of human fetal testis. We identify pre-pachytene piRNAs with features of secondary amplification that map most abundantly to the long interspersed element type 1 (L1) family of TEs. L1-ORF1p expression is heterogeneous in fetal germ cells, peaks at mid-gestation and declines concomitantly with increases in piRNAs, nuclear localization of HIWI2 and an increase in H3K9me3. Surprisingly, the same cells with accumulation of L1-ORF1p display highest levels of HIWI2 and H3K9me3. Conversely, the earliest germ cells with high levels of L1-ORF1p express low levels of the chaperone HSP90α. We propose that a subset of germ cells resists L1 expression, whereas L1-expressing germ cells activate the repression pathway that leads to epigenetic silencing of L1 via H3K9me3.
发育过程中生殖细胞中的表观遗传重置使转座元件（TEs）去抑制。piRNA 通过靶向 mRNA 破坏和抑制性表观遗传标记的沉积来保护胎儿生殖细胞。在这里，我们提供了人类胎儿睾丸生殖细胞中活跃的 piRNA 途径和 TE 抑制的第一个证据。我们鉴定了具有二次扩增特征的精母细胞前 piRNA，这些 piRNA 最丰富地映射到长散布元件 1 型（L1）TE 家族。胎儿生殖细胞中 L1-ORF1p 的表达具有异质性，在妊娠中期达到高峰，并随着 piRNA 的增加、HIWI2 的核定位和 H3K9me3 的增加而下降。令人惊讶的是，积累 L1-ORF1p 的相同细胞显示出最高水平的 HIWI2 和 H3K9me3。相反，最早具有高水平 L1-ORF1p 的生殖细胞表达低水平的伴侣 HSP90α。我们提出，一部分生殖细胞抵抗 L1 的表达，而表达 L1 的生殖细胞激活抑制途径，导致通过 H3K9me3 使 L1 发生表观遗传沉默。
