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Germline and Somatic Imprinting in the Nonhuman Primate Highlights Species Differences in Oocyte Methylation

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Germline and Somatic Imprinting in the Nonhuman Primate Highlights Species Differences in Oocyte Methylation Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research Germline and somatic imprinting in the nonhuman primate highlights species differences in oocyte methylation Clara Y. Cheong,1 Keefe Chng,1,3 Shilen Ng,1,4 Siew Boom Chew,1,5 Louiza Chan,1 and Anne C. Ferguson-Smith1,2 1Growth, Development and Metabolism Program, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A-STAR), Singapore 117609; 2Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom Genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. Defects in normal im- printing are found in cancer, assisted reproductive technologies, and several human syndromes. In mouse models, germline- derived DNA methylation is shown to regulate imprinting. Though imprinting is largely conserved between mammals, spe- cies- and tissue-specific domains of imprinted expression exist. Using the cynomolgus macaque (Macaca fascicularis) to assess primate-specific imprinting, we present a comprehensive view of tissue-specific imprinted expression and DNA methylation at established imprinted gene clusters. For example, like mouse and unlike human, macaque IGF2R is consistently imprinted, and the PLAGL1, INPP5F transcript variant 2, and PEG3 imprinting control regions are not methylated in the macaque germline but acquire this post-fertilization. Methylome data from human early embryos appear to support this finding. These sug- gest fundamental differences in imprinting control mechanisms between primate species and rodents at some imprinted do- mains, with implications for our understanding of the epigenetic programming process in humans and its influence on disease. [Supplemental material is available for this article.] Genomic imprinting is an epigenetically regulated process result- are also imprinted in marsupials, while no imprinting has been re- ing in gene expression from specific parental alleles. Many im- ported in the egg-laying monotreme mammals to date (Killian printed genes are clustered and feature both protein-coding and et al. 2000; Edwards et al. 2008; Smits et al. 2008; Renfree et al. noncoding RNA genes (Edwards and Ferguson-Smith 2007). In 2009a,b). While the mouse is an informative proxy for human im- mouse, differential DNA methylation at CpG-rich imprinting con- printed gene regulation, not all loci show conserved imprinting, trol regions (ICRs) is first established in gametogenesis, along with notably in the placenta (Tycko and Morison 2002; Morison et al. other methylation marks, and depends on the presence of DNA 2005). Distinct differences in placental evolution, physiology, methyltransferases (DNMTs) (Li et al. 1993; Okano et al. 1999; Li and reproductive biology of the primate and murine groups may andSasaki2011).Duringpreimplantationdevelopment,protection be responsible. In contrast to an evolutionary distance of 75 mil- from demethylation is essential at imprints (Li et al. 2008; Hanna lion years between mouse and human, the macaque diverged 25 and Kelsey 2014),and subsequently,additionaldifferentiallymeth- million years ago from human and shares many physiological sim- ylated regions (DMRs) can become established in response to the ilarities with humans. The added availability of the macaque ge- germline DMR (Kafri et al. 1992; Brandeis et al. 1993a,b). nome has made this nonhuman primate a useful model for Imprinted genes are involved in both pre- and post-natal understanding recent genomic evolutionary changes (Waterston growth, and metabolic and cognitive processes (Ferguson-Smith et al. 2002; Rhesus Macaque Genome Sequencing and Analysis 2011; Cleaton et al. 2014). In humans, aberrant imprinting is re- Consortium et al. 2007; Yan et al. 2011), with further potential sponsible for certain developmental disorders with parental origin for understanding the evolution of epigenetic mechanisms. effects (Weksberg et al. 2003; Gicquel et al. 2005), while perturbed In order to explore the evolution of imprinting in the pri- imprinting is regularly reported in cancers (Uribe-Lewis et al. 2011). mate, we surveyed established imprinted gene clusters for the con- More recently, the increased incidence of imprinting defects in in- servation of imprinted gene expression and DNA methylation in fants conceived through assisted reproduction techniques empha- the nonhuman primate, cynomolgus macaque (Macaca fascicula- sizes the importance of imprinting epigenetics from a very early ris). The closely related cynomolgus and rhesus (Macaca mulatta) developmental time point (Grace and Sinclair 2009). macaques are 99.6% similar, estimated to diverge by only ∼2 mil- Comparative analysis of imprinting between eu-, meta- and lion years, and share much genomic structure and similarity, both prototherian mammals suggests that imprinting arose relatively with each other and with the human genome (Hayasaka et al. recently at most loci—only a few imprinted genes in eutherians 1996; Osada et al. 2008). As such, both are widely used in Present addresses: 3Crown Bioscience, Inc., Santa Clara, CA 95054, © 2015 Cheong et al. This article is distributed exclusively by Cold Spring USA; 4Health Sciences Authority, Singapore 138623; 5Syngenta Harbor Laboratory Press for the first six months after the full-issue publication APAC Pte Ltd., Singapore 117406. date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it Corresponding author: [email protected] is available under a Creative Commons License (Attribution-NonCommercial Article published online before print. Article, supplemental material, and publi- 4.0 International), as described at http://creativecommons.org/licenses/ cation date are at http://www.genome.org/cgi/doi/10.1101/gr.183301.114. by-nc/4.0/. 25:1–13 Published by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/15; www.genome.org Genome Research 1 www.genome.org Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Cheong et al. preclinical studies and are useful models for accessing tissues oth- Maternally imprinted genes erwise limited in human research (Bourne 1975). Here, we provide the most comprehensive survey of imprint- Adjacent to the IGF2-H19 cluster, the KCNQ1 locus also retains ing in the nonhuman primate to date and investigate the conser- its gene order and chromosomal syntenic homology between vation of primary and secondary DMRs between primates and human, macaque, and mouse (Supplemental Fig. 3). Macaque rodents. Our findings suggest that aspects of imprinting control KCNQ1 and SLC22A18 are largely monoallelically expressed in pla- may differ between rodent and macaque, with important implica- centa, with a number of individuals showing preferential but in- tions for epigenetic programming in normal development and complete monoallelic expression at KCNQ1. KCNQ1 expression disease. was, however, biallelic in adult tissues (Fig. 1B). In mouse, imprint- ed expression of Kcnq1 is seen in embryos, but not in adult mice or Results humans. This embryonic stage-specific expression may also be true in primates and could account for the partial imprinting seen in Conservation of allelic expression at imprinted term extraembryonic tissues (Lee et al. 1997; Caspary et al. 1998; loci in macaque Gould and Pfeifer 1998). Published findings on human SLC22A18 suggest that polymorphic imprinting is evident in adult liver and We examined somatic and extraembryonic tissues for allelic ex- kidney (Dao et al. 1998; Gallagher et al. 2006), though the popula- pression at a total of 32 genes known to be imprinted in either hu- tion frequency of this occurrence is unknown. Our analysis of man or mouse. Macaque genomic regions analyzed were identified SLC22A18 in macaques in these same tissues showed consistent by orthology to known human imprinted genes, since the se- biallelic expression (Fig. 1B). quence identity between human and macaque is ∼93% (Rhesus The KCNQ1 locus further highlights that gene-ICR proximity Macaque Genome Sequencing and Analysis Consortium et al. alone does not determine imprinted expression. CDKN1C, a cy- 2007), enabling reference gene mapping and the discovery of nov- clin-dependent kinase inhibitor, is positioned downstream from el polymorphisms required for allele-specific expression analysis. the intronic KvDMR and showed monoallelic expression in cyno- molgus adult tissues. No informative extraembryonic tissues were Paternally imprinted genes available. In mouse, Cdkn1c has a somatic promoter DMR which In mouse, the Igf2-H19 and Dlk1-Dio3 domains are controlled by may contribute to stable monoallelic expression of this gene paternal-specific germline methylation imprints at their inter- (Nowak et al. 2011), though we did not find evidence for this genic ICRs (Kobayashi et al. 2000; de la Puente et al. 2002; DMR in the primate (data not shown). Further examination of cy- Takada et al. 2002; Gabory et al. 2006; Cai and Cullen 2007). Con- nomolgus CDKN1C transcripts also revealed a novel transcript sistent with neonatal rhesus tissues and ES cells, IGF2 and H19 variant with no precedent in human or mouse CDKN1C are monoallelically expressed in all cynomolgus extraembry- (Supplemental Fig. 4; Nielsen et al. 2005). The genomic sequence onic tissues analyzed (Fujimoto et al. 2005, 2006). H19 expression of CDKN1C is conserved between rhesus, cynomolgus, and hu- is also consistently monoallelic in all somatic
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