LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo

Abstract

After fertilization, to initiate development, gametes are reprogramed to become totipotent. Approximately half of the mammalian genome consists of repetitive elements, including retrotransposons, some of which are transcribed after fertilization. Retrotransposon activation is generally assumed to be a side effect of the extensive chromatin remodeling underlying the epigenetic reprogramming of gametes. Here, we used a targeted epigenomic approach to address whether specific retrotransposon families play a direct role in chromatin organization and developmental progression. We demonstrate that premature silencing of LINE-1 elements decreases chromatin accessibility, whereas prolonged activation prevents the gradual chromatin compaction that occurs naturally in developmental progression. Preventing LINE-1 activation and interfering with its silencing decreases developmental rates independently of the coding nature of the LINE-1 transcript, thus suggesting that LINE-1 functions primarily at the chromatin level. Our data suggest that activation of LINE-1 regulates global chromatin accessibility at the beginning of development and indicate that retrotransposon activation is integral to the developmental program.

A lncRNA-like Role for LINE1s in Development

“…In late 2C-stage and 4-cell embryos, LINE1 KD caused reactivation of 2C genes, indicating the ongoing requirement of LINE1 to repress the 2C transcriptional program in early embryogenesis. LINE1 KD also led to strongly reduced zygotic genome activation, another observation consistent with Jachowicz et al (2017). In sum, these studies support a model whereby pervasive LINE1 transcription and LINE1 transcripts themselves play an important role in early developmental gene and chromatin regulation.…”

“…LINE1 KD in 2C embryos reduced chromatin accessibility and increased levels of heterochromatin (Figure 1A), a result that parallels that of Jachowicz et al (2017). In late 2C-stage and 4-cell embryos, LINE1 KD caused reactivation of 2C genes, indicating the ongoing requirement of LINE1 to repress the 2C transcriptional program in early embryogenesis.…”

“…Few studies, however, have evaluated the role of TE transcripts in cellular processes. In a recent issue of Cell , Percharde et al (2018) used antisense oligos as a tool to deplete long interspersed nuclear element 1 (LINE1) transcripts in embryonic stem cells (ESCs) and preimplantation mouse embryos as a complementary but distinct approach to the transcriptional silencing of LINE1 recently performed by Jachowicz et al (2017). The latter paper utilized KRAB-domain fused transcription activator-like effectors (TALEs).…”

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

“…Perhaps due to the association of LINE1 RNA with euchromatin as determined by in situ hybridization, the expression of LINE1 appears to regulate global chromatin accessibility. LINE1 RNA knockdown or transcriptional inhibition leads to global reductions in DNA accessibility . This effect is not rescued by exogenous injection of LINE1 mRNA, suggesting a role for nuclear LINE1 RNA in cis .…”

“…LINE1 RNA is abundant within the nuclei of ESCs and cancer cells, in contrast to LINE1 Orf1p protein . LINE1 is highly expressed in preimplantation embryos and downregulated upon differentiation (Figure ) . Despite its abundance, LINE1 appears to be under tight dosage regulation, with either its repression or overexpression resulting in a reduction in blastocyst formation .…”