Evolution of imprinting via lineage-specific insertion of retroviral promoters

Abstract

26Imprinted genes are expressed from a single parental allele. In mammals, this unusual mode of 27 transcription generally depends on the epigenetic silencing of one allele by DNA methylation 28 (DNAme) established in the germline. While many species-specific imprinted orthologues have been 29 documented in eutherians, the molecular mechanisms underlying the evolutionary switch from biallelic 30 to imprinted expression are currently unknown. During mouse oogenesis, gametic differentially 31 methylated regions (gDMRs) acquire DNAme in a process guided by transcription. Here we show that 32 transcription initiating in proximal lineage-specific endogenous retroviruses (ERVs) is likely 33 responsible for DNAme established in oocytes at 4/6 mouse-specific and 17/110 human-specific 34 maternal imprinted gDMRs (igDMRs). The latter can be further divided into Catarrhini (Old World 35 monkeys and apes)-or Hominoidea (ape)-specific igDMRs, which are embedded within transcription 36 units initiating in ERVs specific to these primate lineages. Using CRISPR-Cas9 mutagenesis, we 37 deleted the relevant murine-specific ERVs upstream of the maternally methylated genes Impact and 38Slc38a4. Strikingly, imprinting at these genes was lost in the offspring of females harboring these 39 deletions and biallelic expression was observed. Our work reveals a novel evolutionary mechanism 40 whereby maternally silenced genes arise from biallelically expressed progenitors. 41 42 43 During postnatal oocyte growth in mammals, transcribed genomic regions acquire two characteristic 44 epigenetic marks: transcription-coupled trimethylation at lysine 36 of histone H3 (H3K36me3) 1 and 45 DNAme 2-5 . In both human and mouse female germline, the overall levels of CpG methylation increase 46 from less than 5% in post-migratory primordial germ cells (PGCs) to ~40-50% in fully-grown, 47 germinal vesicle oocytes (GVOs) 4,6-8 Kobayashi:2013ia}. In growing murine oocytes, 85-90% of this 48 DNAme is deposited over H3K36me3-marked transcribed regions of the genome 3 . Notably, we 49 recently demonstrated that SETD2-dependent deposition of H3K36me3 is required for de novo 50 3 DNAme of transcribed gene bodies in mouse oocytes 9 . Such transcription-coupled de novo DNAme is 51 also responsible for the establishment of regions of differential DNAme between the mature gametes 52 (gametic differentially methylated regions, gDMRs), a subset of which are maintained throughout 53 preimplantation development. This unique class of gDMRs, the imprinted gDMRs (igDMRs), can 54 direct imprinted paternal allele-specific expression of the gene(s) under their regulation, the imprinted 55 genes 3,10,11 . Importantly, transcription initiating within upstream oocyte-specific promoters has been 56 reported to play a critical role in de novo DNAme at the maternal igDMRs of a number of mouse 57 imprinted genes 3,12-16 , but the evolutionary origin of such promoters remains unexplored. 58 59 Specific families of ERVs, also known as long terminal repeat (LTR) retrotransposons, are 6...

Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals

“…The existence of such an evolutionary struggle is perhaps best exemplified by the emergence of genomic imprinting, or parent-of-origin-specific gene expression, in therian mammals 140 . Transposons, particularly ERVs, have played an important role in the evolution of genomic imprinting as an adaption to parental conflict; many of the cis-elements controlling imprinting status and, in some cases, even the imprinted genes themselves are derived from ERV insertions [141][142][143] . The retroviral origins of genomic imprinting are further illustrated by the use of conserved vertebrate host defense systems, namely DNA methylation and KRAB-ZFPs, to maintain imprint status 144,145 .…”

Tissue-specific usage of transposable element-derived promoters in mouse development

“…Recent evidence also suggests that TEs are significant contributors to the origin of vertebrate long non-coding RNAs [7,24]. Meanwhile, TEs were also found to play roles as promoters in early development [25][26][27][28][29] and some terminally differentiated tissues [30,31].…”

Environmentally sensitive hotspots in the methylome of the early human embryo

“…This may reflect the relatively small proportion of PofOm loci in the set of SoC-CpGs, or factors related to the limited methylome coverage of Illumina arrays. More targeted experimental work is required to determine the extent of SoC effects at imprinted loci, especially given our observation that SoC-CpGs are often proximal to ERV transposable elements that have recently been shown to drive the establishment of germline-derived maternal PofOm 51 . Hotspots with evidence of PofOm could be driven by an environmentally sensitive gain of methylation on the paternal allele that is propagated through development, incomplete reprogramming on the maternal allele leaving residual traces of methylated cytosines, or modest de novo methylation at some later point.…”