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Review
. 2022 Mar 3:13:832983.
doi: 10.3389/fgene.2022.832983. eCollection 2022.

The Evolutionary Advantage in Mammals of the Complementary Monoallelic Expression Mechanism of Genomic Imprinting and Its Emergence From a Defense Against the Insertion Into the Host Genome

Tomoko Kaneko-Ishino  1 , Fumitoshi Ishino  2
Affiliations
Review

The Evolutionary Advantage in Mammals of the Complementary Monoallelic Expression Mechanism of Genomic Imprinting and Its Emergence From a Defense Against the Insertion Into the Host Genome

Tomoko Kaneko-Ishino et al. Front Genet. .

Abstract

In viviparous mammals, genomic imprinting regulates parent-of-origin-specific monoallelic expression of paternally and maternally expressed imprinted genes (PEGs and MEGs) in a region-specific manner. It plays an essential role in mammalian development: aberrant imprinting regulation causes a variety of developmental defects, including fetal, neonatal, and postnatal lethality as well as growth abnormalities. Mechanistically, PEGs and MEGs are reciprocally regulated by DNA methylation of germ-line differentially methylated regions (gDMRs), thereby exhibiting eliciting complementary expression from parental genomes. The fact that most gDMR sequences are derived from insertion events provides strong support for the claim that genomic imprinting emerged as a host defense mechanism against the insertion in the genome. Recent studies on the molecular mechanisms concerning how the DNA methylation marks on the gDMRs are established in gametes and maintained in the pre- and postimplantation periods have further revealed the close relationship between genomic imprinting and invading DNA, such as retroviruses and LTR retrotransposons. In the presence of gDMRs, the monoallelic expression of PEGs and MEGs confers an apparent advantage by the functional compensation that takes place between the two parental genomes. Thus, it is likely that genomic imprinting is a consequence of an evolutionary trade-off for improved survival. In addition, novel genes were introduced into the mammalian genome via this same surprising and complex process as imprinted genes, such as the genes acquired from retroviruses as well as those that were duplicated by retropositioning. Importantly, these genes play essential/important roles in the current eutherian developmental system, such as that in the placenta and/or brain. Thus, genomic imprinting has played a critically important role in the evolutionary emergence of mammals, not only by providing a means to escape from the adverse effects of invading DNA with sequences corresponding to the gDMRs, but also by the acquisition of novel functions in development, growth and behavior via the mechanism of complementary monoallelic expression.

Keywords: complementation; evolutionary trade-off; genome innovation; host defense hypothesis; insertion of exogenous DNA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The reciprocal ON-OFF switch of PEG and MEG. In imprinted regions, PEG and MEG cannot be co-expressed in cis. In the insulator model, they are reciprocally regulated by the DNA methylation status of the gDMR including the insulator sequence. An insulator binding protein, such as CTCF, interrupts the downstream enhancer activity, leading to a repression of Genes A and B without any effect on Gene C. In contrast, DNA methylation on the insulator sequence inhibits the binding of the CTCF protein, leading to the induction of the Genes A and B concurrently with repression of the Gene C via DNA methylation on its promoter contiguous to the insulator sequence. The blue and red boxesindicate paternally and maternally active alleles, respectively, while the gray boxes indicate repressed alleles. Then, the blue and red arrows indicate PEG and MEG expression, respectively. The white and black circles indicate non-methylated and methylated CpGs, repressively. This is an updated version of Figure 2 in the previous review (Kaneko-Ishino and Ishino 2019).
FIGURE 2
FIGURE 2
Cycle of genomic imprinting memory. Top: Sperm (left) and oocytes (right) have imprinted memories to express only PEGs and MEGs in somatic cells. Their expression patterns here represent those of androgenetic and parthenogenetic embryos, respectively. Second: The expression profiles of the imprinted genes in paternal and maternal imprinted regions in somatic cells and PGCs until at most day 10.5 (Miki et al., 2005; Yamazaki et al., 2005) This is reestablished by a combination of the sperm and oocyte patterns. Bottom: The expression profiles of imprinted genes in the default states of genomic imprinting (i.e., without any DNA methylation), such as day 12.5 PGC cloned embryos. The black, blue and red circles represent normal biallelic, paternally and maternally expressed genes, respectively. There are two types of imprinted regions, paternally (blue) and maternally imprinted (pink) reginos, in which gDMRs are methylated paternally and maternally, respectively. The erasure of imprinted memories in PGCs occurs around d10.5 and completed by d12.5, then gDMR methylation in the paternally imprinted regions (Paternal imprinting) occurs during prospermatogonia development around the time of birth, while that in the maternally imprinted regions (Maternal imprinting) occurs during oocyte maturation (arrows from the bottom to top). PEG and MEG cannot be co-expressed in cis in any stages of this cycle.
FIGURE 3
FIGURE 3
The emergence of gDMR sequences coincides with the onset of imprinted regulation in mammals. In most cases, the emergence of gDMR sequences, the DNA sequences corresponding to the gDMRs, correlate well with the establishment of imprinted regions in mammalian evolution. The arrowheads indicate when each gDMR sequence appeared in the mammalian lineage tree. Blue and red represent that imprinted regulation started as the paternally and maternally imprinted regions, respectively. Pink represents the maternally imprinted regions in which the emergence of DMR sequences preceded the onset of imprinted regulation, for example, SLC38A4-and SNRPN-DMRs (see the text for the details). It should be noted that mouse Slc38a4 has recently been recognized as an imprinted gene regulated by both canonical and non-canonical imprinting mechanisms (Okae et al., 2014; Inoue et al., 2017a; Bogutz et al., 2019). This is an updated version of Figure 6 in our previous review (Kaneko-Ishino and Ishino 2019).
FIGURE 4
FIGURE 4
Molecular mechanisms underlying how gDMRs are established and maintained. (A) Expression of oocyte-specific transcripts from alternative promoters including LTRs. Oocyte-specific alternative upstream transcripts (dashed arrows) run through the gDMR (a pink box) within gene bodies with deposition of H3K36me3 (yellow trapezoids). In some cases, LTRs are used as the promoters for such transcripts (light blue boxes). (B) DNA methylation in gene body regions including maternal gDMRs. The H3K36me3 epigenetic mark guides DNA methylation in the oocytes, leading to the gene body DNA methylation. There are many more differential methylated CpG sequences than gDMRs in oocytes. (C) Protection of gDMR DNA methylation from a global DNA demethylation wave. Most of the differentially methylated CpG sequences disappear during preimplantation development due to a global DNA demethylation wave (right), however, both maternal and paternal gDMRs remain protected by a large complex including either ZFP57 or ZNF445, members of the KRAB-ZFPs playing an essential role in repressing invaded retroviruses (left and center). (D) The resulting canonical imprinted regions. Double-headed arrows indicate a therian-/eutherian-specific (left) and a species-specific (center) imprinted region in somatic cells. The gDMR DNA methylation is maintained during postimplantation period by symmetric CpG methylation catalyzed by DNMT1 included in the KRAB-ZFPs complex. The differential recognition mechanisms in the paternal and maternal germ cells lead to the imprinted region in somatic cells.
FIGURE 5
FIGURE 5
Generation of a novel canonical imprinted region. (A) Before an insertion event. A chromosomal region comprising three non-imprinted evolutionary resident Genes A, B and C. A downstream enhancer sequence (green) regulates the activation of the three genes. (b) Insertion of a large DNA fragment (yellow) containing an insulator sequence as a critical cis-element (pink) and a novel gene (orange) between Genes B and C. The insertion event leads to the repression of Genes A and B via the insulator function (see Figure 1). The novel added gene is expressed from the newly integrated DNA fragment in addition to Gene C. (C) DNA methylation on the inserted insulator in oocyte. Emergence of an upstream promotor (light blue) that expresses an oocyte-specific alternative transcript (dashed line). This transcript goes through the insulator, leading to DNA methylation on the insulator in an oocyte-specific manner. (D) Expression of a newly added gene from paternal allele of a novel imprinted region (arrow), while Genes A and B from maternal allele because the gDMR in the paternally-derived chromosome is not DNA methylated.
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