Genomic Imprinting, Action, and Interaction of Maternal and Fetal Genomes
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Genomic imprinting, action, and interaction of maternal and fetal genomes Eric B. Keverne1 Sub-Department of Animal Behaviour, University of Cambridge, Cambridge CB23 8AA, United Kingdom Edited by Donald W. Pfaff, The Rockefeller University, New York, NY, and approved October 16, 2014 (received for review July 9, 2014) Mammalian viviparity (intrauterine development of the fetus) and striatum (4). Moreover, the growth of the brain in parthe- introduced a new dimension to brain development, with the fetal nogenetic chimeras was enhanced by this increased gene dosage hypothalamus and fetal placenta developing at a time when the from maternally expressed alleles, whereas the brains of an- fetal placenta engages hypothalamic structures of the maternal drogenetic chimeras were smaller, especially relative to body generation. Such transgenerational interactions provide a basis for weight (3). These spatially distinct anatomical outcomes matched ensuring optimal maternalism in the next generation. This success to those brain regions found to be affected in human clinical has depended on genomic imprinting and a biased role of the studies on brain dysfunction seen in Prader–Willi and Angelman’s matriline. Maternal methylation imprints determine parent of origin syndromes (5, 6). The uniparental disomies of restricted chromo- expression of genes fundamental to both placental and hypotha- somal regions found in these clinical disorders were congruent lamic development. The matriline takes a further leading role for with the neural distribution of the chimeric cells. transgenerational reprogramming of these imprints. Developmen- Since these early findings, ∼100 genes have been identified tal errors are minimized by the tight control that imprinted genes to be “imprinted,” the majority of which have been shown to be have on regulation of downstream evolutionary expanded gene expressed in the placenta (7). Interestingly, a number of these families important for placental and hypothalamic development. placental genes have also been shown to be expressed in the de- Imprinted genes themselves have undergone purifying selection, veloping hypothalamus, most of which are maternally imprinted providing a framework of stability for in utero development with and paternally expressed and many of which influence cell pro- most growth variance occurring postnatally. Mothers, not fathers, liferation, cell cycle arrest, and apoptosis (Table 1). It is these take the lead in the endocrinological and behavior adaptations that placental/hypothalamic coexpressed imprinted genes and the nurture, feed, and protect the infant. In utero coadaptive develop- networks they regulate that are of special interest to a consideration ment of the placenta and hypothalamus has thus required a con- of mammalian brain development and its evolution. comitant development to ensure male masculinization. Only placental male mammals evolved the sex determining SRY, which activates Genomic Imprinting Sox9 for testes formation. SRY is a hybrid gene of Dgcr8 expressed There has been a strong bias for the matriline in determining the in the developing placenta and Sox3 expressed in hypothalamic evolutionary reproductive success of mammals, primarily through development. This hybridization of genes that take their origin the disproportionate investment shown by females in pregnancy, from the placenta and hypothalamus has enabled critical in utero in postnatal nurturing, and in maternal care for offspring. Geno- timing for the development of fetal Leydig cells, and hence tes- mic imprinting has not been found in egg-laying monotreme tosterone production for hypothalamic masculinization. mammals, and there are relatively few genes recruited to the imprint control regions (ICRs) of those marsupials with a genomic imprinting | genomic reprogramming | hypothalamus | short-lived chorio-vitelline placenta (8). Thus, fewer genes with placenta | development imprinted expression are observed in marsupials (six to date), and all are expressed in the placenta, whereas a number of genes enomic imprinting is an unusual epigenetic process in that imprinted in the eutherian placenta are expressed but not Git is heritable and results in autosomal gene expression imprinted in the marsupial placenta. The evolutionary trend has according to parent of origin. The recognition of genomic im- been to increase the number of heritable ICRs or differentially printing as a prominent feature of mammalian development came methylated region (DMRs) and at the same time increase the about through the generation of diploid mouse embryos with two number of genes recruited to these ICRs/DMRs. The ICRs are copies of maternal (parthenogenetic) or two copies of paternal particularly important for monoallelic regulation of gene dosage (androgenetic) genomes (1, 2). Although the developmental out- as revealed by the disrupted phenotypes when perturbations are comes of these maternal and paternal disomies produced differ- seen in the ICR but without any changes to the genes that are ences in placental size (1, 2), both procedures were lethal before imprinted. Such ICR perturbations are seen in a subset of the brain development. A significant experimental approach to in- human syndromes for Prader–Will and Angelman’s syndrome (9). vestigating genomic imprinting in the brain was first achieved by ICRs act on clusters of genes (3–12 in mouse) and typically in- the construction of chimeras (3, 4). Mouse embryos constructed clude a long noncoding RNA (lncRNA). The lncRNA is usually from a mixture of cells that were either androgenetic/normal or expressed from the opposite parental chromosome to the pro- parthenogenetic/normal survived, provided that these disomic tein coding RNA, but a common regulatory theme with respect cells were not greater than 40% of total cells. The precise loca- tions in the brain to which these chimeric cells participate was made possible to observe by the insertion of a LacZ or multiple β This paper results from the Arthur M. Sackler Colloquium of the National Academy of copies of the -globin gene marker. At birth, the neural cells that Sciences, “Epigenetic Changes in the Developing Brain: Effects on Behavior,” held March were disomic for paternal alleles contributed substantially to those 28–29, 2014, at the National Academy of Sciences in Washington, DC. The complete pro- regions of the brain engaged with primary motivated behavior gram and video recordings of most presentations are available on the NAS website at (hypothalamus, medial preoptic area (MPOA), bed nucleus of www.nasonline.org/Epigenetic_changes. stria terminalis and amygdala (BNST), and amygdala) and were Author contributions: E.B.K. designed research, performed research, and wrote the paper. excluded from the developing cortex and striatum. In contrast, The author declares no conflict of interest. parthenogenetic cells were excluded from these hypothalamic This article is a PNAS Direct Submission. regions of the brain but selectively accumulated in the neocortex 1Email: [email protected]. 6834–6840 | PNAS | June 2, 2015 | vol. 112 | no. 22 www.pnas.org/cgi/doi/10.1073/pnas.1411253111 Downloaded by guest on September 30, 2021 PAPER Table 1. Imprinted gene expression in placenta and developmental integrity, forming the development foundations COLLOQUIUM hypothalamus on which the nonimprinted genome builds. Imprint control re- Gene Molecular actions Cellular actions gions have a sexual dimorphism in that they are predominantly matrilineal and have significant effects for embryo survival early Grb10 (P) (M) Maternal expression: Apoptosis in development, primarily by pathways concerned with mother/ placenta; paternal fetus interactions (16). The reproductive success of mammals expression; hypothalamus also places a considerable burden on matrilineal time and en- Phlda2 (M) Placental Apoptosis ergy, with some 95% of mammalian female adult life committed growth/neuroendocrine to pregnancy, lactation, and maternal care. Because stability and tumors purifying selection are features of imprinted genes, and matri- P57 kip2 (M) Tumor suppressor Cell cycle regulation; lineal ICRs result primarily in paternal expression, the question cdk inhibitor arises as to how gene stability survived the mutagenic environ- Dlk (P) Interacts with Igf1 binding Cell cycle ment of spermatogenesis. Point mutations, expanded tandem protein arrest/apoptosis repeats, and structural chromosomal mutations usually pre- Gnas (P) YY1 binding/activates Energy homeostasis dominate through patrilineal transmission (17). However, the adenylyl cyclase sperm genome is tightly packaged with protamines and not ini- Magel2 (P) MAGE family of proteins Apoptosis tially available for transcription following fertilization. Post- Necdin (P) Regulates Hif1α/Arnt Apoptosis fertilization male chromatin is remodeled from the nucleoprotamine 2+ Nnat (P) Phosphorylates CREB Increase intracell Ca state to the nucleohistone state, and at the nuclear replication β Peg1 (P) Hydrolase fold family Growth regulation phase (E2–3), sperm DNA undergoes mismatch repair (18). The Peg3 (P) YY1 binding/regulates Apoptosis mammalian zygote has several unique features influencing DNA α Hif1 /Arnt repair depending on proteins and mRNAs of maternal origin in Zac1 (P) Bind to Igf2 enhancer Cell cycle the oocyte. Maternal and paternal chromatin at this zygotic arrest/apoptosis stage is epigenetically very dissimilar, with male chromatin un- dergoing widespread demethylation linked to DNA repair mechanisms (19).