Chromatin signatures and retrotransposon profiling in mouse embryos reveal regulation of LINE-1 by RNA

Abstract

How a more plastic chromatin state is maintained and reversed during development is unknown. Heterochromatin-mediated silencing of repetitive elements occurs in differentiated cells. Here, we used repetitive elements, including retrotransposons, as model loci to address how and when heterochromatin forms during development. RNA sequencing throughout early mouse embryogenesis revealed that repetitive-element expression is dynamic and stage specific, with most repetitive elements becoming repressed before implantation. We show that LINE-1 and IAP retrotransposons become reactivated from both parental genomes after fertilization. Chromatin immunoprecipitation for H3K4me3 and H3K9me3 in 2- and 8-cell embryos indicates that their developmental silencing follows loss of activating marks rather than acquisition of conventional heterochromatic marks. Furthermore, short LINE-1 RNAs regulate LINE-1 transcription in vivo. Our data indicate that reprogramming after mammalian fertilization comprises a robust transcriptional activation of retrotransposons and that repetitive elements are initially regulated through RNA.

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

“…In oocytes, predominantly ERVL-MaLRs and, to a lesser extent, ERVK retrotransposons are transcribed. These elements also control gene expression through formation of chimearic transcripts (Fadloun et al, 2013;Peaston et al, 2004;Svoboda et al, 2004;Veselovska et al, 2015). In early embryos, ERVL, ERVK and ERV1 retrotransposons, as well as LINEs, are more highly expressed than ERVL-MaLRs (Fadloun et al, 2013;Ribet et al, 2008).…”

ATRX contributes to epigenetic asymmetry and silencing of major satellite transcripts in the maternal genome of the mouse embryo

“…In the mammalian embryo, establishment and maintenance of pericentric heterochromatin (PCH) takes place during the first cleavage divisions and require extensive genome reprogramming. For example, deposition of the histone variant H3.3 and a burst of transcription of non-coding RNAs from major satellite sequences at the two-cell stage induce global remodeling and association of PCH domains into the nascent chromocenters of blastomere interphase nuclei (Probst et al, 2010;Santenard et al, 2010;Almouzni and Probst, 2011;Probst and Almouzni, 2011;Fadloun et al, 2013). Importantly, histone H3.3 is required at the early zygote stage to regulate ribosomal RNA transcription as well as chromatin condensation at the two-cell stage (Lin et al, 2013(Lin et al, , 2014.…”

Consequences of ongoing retrotransposition in mammalian genomes

“…L1 RNA is present in human and rodent germ cells (male and female), embryonic stem (ES) cells, neural progenitor cells, cancer cells/tumors, in mouse preimplantation embryos, and in a variety of human somatic tissues. [29][30][31][32][33][34][35][36][37][38] In addition, L1 RNA is more abundant in normal human fibroblasts late during senescence ex vivo and in skeletal muscle and liver of aged mice. 39,40 However, many transcripts are partial-length, which can arise from premature termination at multiple internal polyadenylation signal sequences and from splicing.…”

“…L1 and IAP are enriched for the activating mark, histone H3 lysine 4 trimethylation (H3K4me3), and the repressive mark, H3K9me3, when they are expressed at the two-cell stage, but are only enriched for H3K9me3 at the eight-cell stage as expression begins to decrease. 38 [141][142][143] In contrast, mouse LTR retrotransposons are not more highly expressed in mouse embryonic fibroblasts (MEFs) deficient for Setdb1, are enriched for H4K20me3, but not H3K9me3, in mouse fibroblast cell lines, and are silenced by Dnmt1 in postimplantation embryos. 142,144 L1 promoters are silenced by H3K9me3 and H4K20me3 in MEFs dependent on binding of retinoblastoma protein family members to L1.…”

“…23,45 IAP RNA is present in male germ cells, oocytes, ovulated eggs, very early embryos, and at reduced levels as preimplantation development progresses. 28,38,[46][47][48] Limited somatic expression of IAP may be restricted to particular individual elements based on their genomic context. 23 MusD transcripts are expressed early in embryogenesis, at reduced levels as embryogenesis proceeds, in mouse ES cells, and at elevated levels in skeletal muscle and liver of aged mice.…”