Epigenetic Control of Retrotransposon Expression in Human Embryonic Stem Cells

Abstract

Long interspersed element 1s (LINE-1s or L1s) are a family of non-long-terminal-repeat retrotransposons that predominate in the human genome. Active LINE-1 elements encode proteins required for their mobilization. L1-encoded proteins also act in trans to mobilize short interspersed elements (SINEs), such as Alu elements. L1 and Alu insertions have been implicated in many human diseases, and their retrotransposition provides an ongoing source of human genetic diversity. L1/Alu elements are expected to ensure their transmission to subsequent generations by retrotransposing in germ cells or during early embryonic development. Here, we determined that several subfamilies of Alu elements are expressed in undifferentiated human embryonic stem cells (hESCs) and that most expressed Alu elements are active elements. We also exploited expression from the L1 antisense promoter to map expressed elements in hESCs. Remarkably, we found that expressed Alu elements are enriched in the youngest subfamily, Y, and that expressed L1s are mostly located within genes, suggesting an epigenetic control of retrotransposon expression in hESCs. Together, these data suggest that distinct subsets of active L1/Alu elements are expressed in hESCs and that the degree of somatic mosaicism attributable to L1 insertions during early development may be higher than previously anticipated.

Analysis of the human immunodeficiency virus-1 RNA packageome

“…The primers used to detect consensus L1Hs were described (Wissing et al 2012). The primers used to detect AluY sequences were modified from previously described primers (Macia et al 2011). …”

Regulation of Retrotransposition of Long Interspersed Element-1 by Mitogen-Activated Protein Kinases

“…However, 80 to 100 copies of L1 are competent for retrotransposition (L1-RTP) (7), and approximately 10 % of these are highly active for "copy and paste" (7). L1 is actively expressed in embryonal stem cells (8) and L1-RTP is induced in oocytes or early embryonic development (9)(10)(11). L1-RTP occurring in germ lines would function an intrinsic factor responsible for allelic variants among individuals (12,13).…”

Establishment of a genome-wide and quantitative protocol for assessment of transcriptional activity at human retrotransposon L1 antisense promoters

“…Notably, previously reported cloning experiments of L1ASP-driven transcripts were carried out also by 3'RACE, which however used L1ASP-specific primers targeting the region downstream of the two L1ASP splice acceptors (shown by black arrowheads in Fig. 1B) (Cruickshanks and Tufarelli, 2009;Macia et al, 2011). With these primers, only unspliced transcripts (Type I) or transcripts using both splice donor and acceptor within the L1ASP sequence (Types II, III, and IV) could be cloned by RT-PCR.…”

“…While the sense-promoters of any L1s produce a single type of RNA, L1 mRNA, as described above, the antisense-promoters (ASPs) at different L1 loci transcribe RNAs with distinctive 3' sequences (Speek, 2001;Nigumann et al, 2002;Wheelan et al, 2005;Matlik et al, 2006;Cruickshanks and Tufarelli, 2009;Faulkner et al, 2009;Macia et al, 2011;Criscione et al, 2016). Activation of the ASP starts transcription in the middle of the ~900-bp promoter, between nucleotides 379 and 498 relative to the L1 5′ terminus (Yang and Kazazian, 2006) and transcribe the genomic regions flanking to the L1 5'-ends (Fig.…”