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Review
. 2019 Jun;128(2):69-80.
doi: 10.1007/s00412-018-00690-5. Epub 2019 Feb 5.

Maternal regulation of chromosomal imprinting in animals

Prim B Singh  1   2 , Victor V Shloma  3   4 , Stepan N Belyakin  3   4
Affiliations
Review

Maternal regulation of chromosomal imprinting in animals

Prim B Singh et al. Chromosoma. 2019 Jun.

Abstract

Chromosomal imprinting requires an epigenetic system that "imprints" one of the two parental chromosomes such that it results in a heritable (cell-to-cell) change in behavior of the "imprinted" chromosome. Imprinting takes place when the parental genomes are separate, which occurs during gamete formation in the respective germ-lines and post-fertilization during the period when the parental pro-nuclei lie separately within the ooplasm of the zygote. In the mouse, chromosomal imprinting is regulated by germ-line specific DNA methylation. But the methylation machinery in the respective germ-lines does not discriminate between imprinted and non-imprinted regions. As a consequence, the mouse oocyte nucleus contains over a thousand oocyte-specific germ-line differentially methylated regions (gDMRs). Upon fertilization, the sperm provides a few hundred sperm-specific gDMRs of its own. Combined, there are around 1600 imprinted and non-imprinted gDMRs in the pro-nuclei of the newly fertilized zygote. It is a remarkable fact that beginning in the maternal ooplasm, there are mechanisms that manage to preserve DNA methylation at ~ 26 known imprinted gDMRs in the face of the ongoing genome-wide DNA de-methylation that characterizes pre-implantation development. Specificity is achieved through the binding of KRAB-zinc finger proteins to their cognate recognition sequences within the gDMRs of imprinted genes. This in turn nucleates the assembly of localized heterochromatin-like complexes that preserve methylation at imprinted gDMRs through recruitment of the maintenance methyl transferase Dnmt1. These studies have shown that a germ-line imprint may cause parent-of-origin-specific behavior only if "licensed" by mechanisms that operate post-fertilization. Study of the germ-line and post-fertilization contributions to the imprinting of chromosomes in classical insect systems (Coccidae and Sciaridae) show that the ooplasm is the likely site where imprinting takes place. By comparing molecular and genetic studies across these three species, we suggest that mechanisms which operate post-fertilization play a key role in chromosomal imprinting phenomena in animals and conserved components of heterochromatin are shared by these mechanisms.

Keywords: Chromosomal imprinting; Epigenetics; Genomic imprinting; Germ-line differentially methylated regions; H3K9me3:HP1:H4K20me3 pathway; Heterochromatin; Mus musculus; Non-coding RNA; Parent-of-origin effects; Plannococcus citri; Sciara coprophila.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Maternal regulation of chromosomal imprinting in mice. a Preservation of methylation at imprinted gDMRs. (1) The paternal (sperm nucleus in blue) and maternal (oocyte nucleus in red) nuclei contain homologous chromosomes that carry CpG islands (CGIs) depicted as rectangles numbered 1 through to 11 on blue (paternal homolog) and red (maternal homolog) lines. Open rectangles represent non-methylated CGIs. Some methylated CGIs are shared (e.g., closed rectangle at position 3 on both parental homologs) and are not gDMRs. Some methylated CGIs are non-imprinted gDMRs (e.g., closed rectangles at position 6 on paternal chromosome and positions 2, 4, 5, 9, and 11 on the maternal chromosome) that will lose their methylation during the DNA demethylation that takes place as embryos pass through preimplantation development. A few methylated CGIs are imprinted gDMRs (closed rectangles at position 10 on the paternal chromosome and 1 and 8 on the maternal homolog) that will retain their methylation status through DNA demethylation. In actuality, there are over a thousand non-imprinted and imprinted gDMRs present in the oocyte nucleus and a few hundred will enter with the sperm (Kobayashi et al. 2012). This difference in number is reflected in the difference in closed rectangles on the maternal (red line) and paternal (blue line) homologs. (2) The maternal (in red) and paternal (in blue) pro-nuclei contain the homologous chromosomes (red and blue lines, respectively) described in (1). Of the ~ 1600 non-imprinted and imprinted gDMRs in the zygote, only a small percentage—the imprinted gDMRs—will preserve DNA methylation in the face of the DNA demethylation that takes place during pre-implantation development (Messerschmidt et al. 2014). The initial assembly of the heterochromatin-like complexes that preserve methylation at imprinted gDMRs takes place in the newly fertilized zygote (see text for details). (3) Preservation of methylation at imprinted gDMRs on the paternal (position 10) and maternal (positions 1 and 8) homologs is due to localized heterochromatin-like complexes at imprinted gDMRs. The complexes preserve DNA methylation at imprinted gDMRs throughout pre-implantation development; non-imprinted gDMRs and methylated CGIs become de-methylated (stippled rectangles). (4) Global levels of DNA methylation reach their lowest point in embryonic nuclei of the blastocyst. However, methylation at imprinted gDMRs is preserved by the heterochromatin-like complexes shown in (3), on the paternal (position 10) and maternal (position 1 and 8) homologs. P denotes paternal homolog and M the maternal homolog. b Assembly of localized heterochromatin-like complex at imprinted gDMRs. Methylation of cytosines in CpG dinucleotides (black circles) is preserved by the assembly of a heterochromatin-like complex at imprinted gDMRs. The complex is targeted by the KRAB zinc-finger protein Zfp57 that binds the hexamer motif TGCCGC when the cytosine in the CpG is methylated (black circle in green rectangle). This in turn recruits KAP1, which is a modular protein that acts as a focal point for the recruitment of Setdb1 histone methyltransferase, HP1, and Dnmt1. HP1 binds the H3K9me3 generated by Setdb1 and recruits a H4K20me3 histone methyl-transferase that generates H4K20me3 thus forming the H3K9me3:HP1:H4K20me3 pathway. DNA methylation at the imprinted gDMR is maintained (dotted lines) by Dnmt1. For a full description of the molecular constituents of the heterochromatin-like complex, see Singh (2016)
Fig. 2
Fig. 2
H3K9me3 and H4K20me3 are enriched at the CE on polytene chromosomes. The bottom two panels show partial polytene chromosomes spreads, where rectangles encompass the termini of the X-chromosomes that were labeled with antibodies specific for H3K9me3 (left) and H4K20me3 (right). In the top row, the left panel is a schematic representation of a polytene X chromosome centromeric end (Crouse et al. ; Gabrusewycz-Garcia 1964). The arrows show the positions of heterochromomeres H3 and H2; H2 contains the CE. The middle panel is a higher magnification of the distribution of H3K9me3 on the polytene X chromosome end. H3K9me3 is enriched on H3 and H2 heterochromomeres. The right panel is a higher magnification of the distribution of H4K20me3 on the polytene X chromosome end. H4K20me3 is enriched on H3 and H2 heterochromomeres. The staining of Sciara coprophila polytene chromоsomes with anti-H3K9me3 and -H4K20me3 antibodies was according to Cowell et al. (2002) and Kourmouli et al. (2004), respectively
Fig. 3
Fig. 3
Maternal regulation of chromosomal imprinting in Sciara coprophila.a Imprinting of a paternal CE in the XX′ maternal ooplasm. In Sciara, two types of egg are fertilized by double-X (XpXp) males (sperm nuclei are given in blue). The first type are eggs laid by XX′ females (top row on left; shaded pink) that will give rise to daughters of the genetic constitution X′mXp or XmXp because eggs conditioned by XX′ mothers eliminate one Xp in the soma. The second type are eggs laid by XX females (second row on left; shaded blue) that will give rise to XmO males because eggs conditioned by XX mothers eliminate both Xps in the soma. The Xm chromosomes are not eliminated. The controlling element (CE) on the X chromosome that is embedded within heterochromomere II adjacent to the X centromere regulates the elimination of Xps. In the top row, a model is presented where the haploid maternal nucleus laid by the XX′ mother contains either an X or X′ chromosome. The maternal CE is rendered inert by the H3K9me3:HP1:H4K20me3 pathway that assembles a heterochromatin-like complex. After the fertilization by the double-X (XpXp) sperm, the paternal pro-nucleus is formed and conditioning of the ooplasm by the XX′ mother results in assembly of heterochromatin-like complex at one of the two paternal CEs rendering it inexpressible, like the maternal CE; the complex is assembled at the CE on the Xp that will later be retained (see Fig. 3b). The remaining paternal CE is an “open” expressible state. The bottom row depicts an egg laid by the XX mother. The maternal CE is again inexpressible due to the assembly of a heterochromatin-like complex, while conditioning of the ooplasm by the XX mother leaves both paternal CEs in an “open” expressible state. The stripes of color at the CE represent H3K9me3 (yellow), H4K20me3 (purple), and HP1 protein (black). Female chromosomes are in red and male are in blue. b A model for the elimination of Xp chromosomes in the embryonic soma. In the top row, the paternal CE on the Xp chromosome that will be eliminated is in an “open” expressible state. This remains so after replication where the sister chromatids become aligned and connected on the metaphase plate before separation to the poles at anaphase. At anaphase, the centromeres separate, but since the CE is active, we suggest that the CE encodes an ncRNA that affects that ability of the sister chromatids to separate. As a consequence, chromatids remain physically bound together on the metaphase plate and are eliminated. The bottom row depicts the situation in embryos that develop from eggs laid by XX′ mothers where one Xp is retained. When an Xp chromosome is retained, the putative ncRNA is not expressed because of the heterochromatin-like complex assembled at the CE. Mitosis then proceeds in the orthodox manner. The chromatids align at the metaphase plate and, first, the centromeres and then the chromosome arms separate. Each chromatid then segregates into one of the daughter nuclei. The model is taken and modified from Singh (2016)
Fig. 4
Fig. 4
Maternal regulation of chromosomal imprinting in coccids. a Heterochromatinization of the paternal chromosome set in coccids. The sperm (nucleus in blue) fertilizes the egg (nucleus in red). The zygote contains 10 chromosomes (2n = 10), which is the typical number found in coccid species. At around the 7th cleavage division in male embryos, a wave of heterochromatinization begins at one of the poles (shown in male embryo beginning at the right-hand pole). Heterochromatinization leads to the formation of a chromocenter (blue) that consists of the aggregation of the paternal chromosome set, which is shown magnified in the inset above the male embryo. The chromocenter is enriched in two heterochromatin-specific histone modifications H3K9me3 (yellow) and H4K20me3 (purple) as well as the non-histone chromosomal protein HP1 protein (black). In the rest of the male embryo individual, paternal (blue) and maternal (red) chromosomes can be observed and there is no chromocenter. This is the case throughout the female embryo given on the left. The “dots” of H3K9me3 (yellow), H4K20me3 (purple), and HP1 protein (black) simply represent enrichment—their distributions overlap on the heterochromatic set in embryos (Bongiorni et al. ; Cowell et al. ; Kourmouli et al. 2004). b The development of parthenogenetic males and females embryos in Pulvinaria hydrangeae. Meiosis gives rise to a haploid maternal nucleus containing 5 chromosomes; chromosomes at all stages are given in red as they are entirely maternal in origin. Polar bodies (PBs) I and II, once extruded, take no part in the events that follow. The maternal nucleus undergoes a haploid mitosis and the products fuse to give a diploid zygote substitute, 95% of which give rise to females where both sets are euchromatic. Five percent of the embryos produce males where one set of chromosomes becomes heterochromatic. Since the males are derived without any paternal contribution, the imprinting leading to subsequent heterochromatinization is therefore under maternal control and determined by conditioning of the maternal ooplasm. c A model for the maternal regulation of imprinting in coccids. In the top row, the maternal nucleus (in red) lies in an oocyte cytoplasm conditioned to produce females after fertilization (sperm nucleus is given in blue). Both chromosome sets remain euchromatic at all stages of development shown. In the bottom row, oocytes conditioned to produce males the egg are spatially differentiated with a region (shaded in blue) that contains factors or determinants laid down by the mother that can “imprint” chromosomes in the paternal pro-nucleus for later heterochromatinization. Heterochromatinzation is depicted as the step-wise aggregation of the paternal chromosomes (blue) into a chromocenter. The maternal chromosomes are colored red
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