Biology subjects

Lorincz, M. C.

Publications and source records attributed to Lorincz, M. C..

4 recordsLinked to original sources

bioRxiv2023

Post-fertilization transcription initiation in an ancestral LTR retrotransposon drives lineage-specific genomic imprinting of ZDBF2

The imprinted ZDBF2 gene is controlled by oocyte-derived DNA methylation, but its epigenetic regulation is quite different from that of other canonically imprinted genes that are dependent on DNA methylation deposited in the gametes. At the ZDBF2 locus, maternal DNA methylation in the imprinted differentially methylated region (DMR) does not persist after implantation. Instead, a transient transcript expressed in the early embryo exclusively from the unmethylated paternal allele of the DMR, known as GPR1-AS in humans and Liz in mice, contributes to establishing secondary DMRs that maintain paternal expression of ZDBF2 in the somatic lineage. While the imprinting of ZDBF2 is evident in humans and mice, whether this process is conserved in other mammals has not been addressed. Here, we show that the first exon of human GPR1-AS overlaps with that of a long terminal repeat (LTR) belonging to the MER21C subfamily of retrotransposons. Although this LTR family appears and is amplified in Boroeutherians, the magnorder of placental mammals that includes the Euarchontoglires and Laurasiatheria superorders, the MER21C insertion into the GPR1-AS orthologous region occurred specifically in the common ancestor of Euarchontoglires, a clade that includes extant primates, rodents, and rabbits. The first exon of mouse Liz does not overlap with an annotated LTR in standard repeat annotation; however, promoter activity assay and multiple sequence alignment suggests that it retains a functionally conserved relationship with the MER21C-overlapping first exon of GPR1-AS. Furthermore, directional RNA sequencing of placental tissues from rabbits and nonhuman primates also revealed GPR1-AS orthologs, with their first exon embedded within the same ancestral LTR. In contrast, allele-specific expression profiling of cow and tammar wallaby, mammals outside the Euarchontoglires group, revealed expression from both alleles in all tissues analyzed. Taken together, these observations suggest that imprinting of ZDBF2 in Euarchontoglires had its genesis in the insertion of a MER21C element in their common ancestor. Our previous studies showed that LTRs reactivated in oocytes contribute to lineage-specific imprinting during mammalian evolution. The data presented here suggest that post-fertilization activation of an ancestral LTR-derived sequence can also contribute to the lineage-specific establishment of imprinted genes.

genomics↗

bioRxiv2022

Conservation and divergence of canonical and non-canonical imprinting in murids

BackgroundGenomic imprinting affects gene expression in a parent-of-origin manner and has a profound impact on complex traits including growth and behaviour. While the rat is widely used to model human pathophysiology, few imprinted genes have been identified in this murid. To systematically identify imprinted genes and genomic imprints in the rat, we used low input methods for genome-wide analyses of gene expression and DNA methylation to profile embryonic and extra-embryonic tissues at allele-specific resolution. ResultsWe identify 14 and 26 imprinted genes in these tissues, respectively, with 10 of these genes imprinted in both tissues. Comparative analyses with mouse revealed that orthologous imprinted gene expression and associated canonical DNA methylation imprints are conserved in the embryo proper of the Muridae family. However, only 3 paternally expressed imprinted genes are conserved in the extra-embryonic tissue of murids, all of which are associated with non-canonical H3K27me3 imprints. The discovery of 8 novel non-canonical imprinted genes unique to the rat is consistent with more rapid evolution of extra-embryonic imprinting. Meta-analysis of novel imprinted genes revealed multiple mechanisms by which species-specific imprinted expression may be established, including H3K27me3 deposition in the oocyte, the birth of ZFP57 binding motifs and the insertion of endogenous retroviral promoters. ConclusionsIn summary, we provide a comprehensive list of imprinted loci in the rat, reveal the extent of conservation of imprinted gene expression, and identify potential mechanisms responsible for the evolution of species-specific imprinting.

genomics↗

bioRxiv2020

Maternal DNMT3A-dependent de novo methylation of the zygotic paternal genome inhibits gene expression in the early embryo

De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. Following fertilization, the paternal genome undergoes widespread DNAme loss before the first S-phase. Paradoxically, recent mass spectrometry analysis revealed that a low level of de novo DNAme occurs exclusively on the zygotic paternal genome. However, the loci involved and impact on genic transcription was not addressed. Here, we employ allele-specific analysis of wholegenome bisulphite sequencing (WGBS) data and show that a number of genomic regions, including several dozen CGI promoters, are de novo methylated on the paternal genome in 2-cell embryos. A subset of these promoters maintains DNAme through development to the blastocyst stage. Consistent with zygotic paternal DNAme acquisition (PDA), many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Strikingly, PDA is lost following maternal deletion of Dnmt3a. Furthermore, a subset of promoters showing PDA which are normally transcribed from the paternal allele in blastocysts show premature transcription at the 4-cell stage in maternal Dnmt3a knockout embryos. These observations uncover an unexpected role for maternal DNMT3A activity in postfertilization epigenetic reprogramming and transcriptional silencing of the paternal genome.

developmental biology↗

bioRxiv2019

Evolution of imprinting via lineage-specific insertion of retroviral promoters

Imprinted genes are expressed from a single parental allele. In mammals, this unusual mode of transcription generally depends on the epigenetic silencing of one allele by DNA methylation (DNAme) established in the germline. While many species-specific imprinted orthologues have been documented in eutherians, the molecular mechanisms underlying the evolutionary switch from biallelic to imprinted expression are currently unknown. During mouse oogenesis, gametic differentially methylated regions (gDMRs) acquire DNAme in a process guided by transcription. Here we show that transcription initiating in proximal lineage-specific endogenous retroviruses (ERVs) is likely responsible for DNAme established in oocytes at 4/6 mouse-specific and 17/110 human-specific maternal imprinted gDMRs (igDMRs). The latter can be further divided into Catarrhini (Old World monkeys and apes)- or Hominoidea (ape)-specific igDMRs, which are embedded within transcription units initiating in ERVs specific to these primate lineages. Using CRISPR-Cas9 mutagenesis, we deleted the relevant murine-specific ERVs upstream of the maternally methylated genes Impact and Slc38a4. Strikingly, imprinting at these genes was lost in the offspring of females harboring these deletions and biallelic expression was observed. Our work reveals a novel evolutionary mechanism whereby maternally silenced genes arise from biallelically expressed progenitors.

genetics↗