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O'Leary EM, Bonthuis PJ. Mom genes and dad genes: genomic imprinting in the regulation of social behaviors. Epigenomics 2025:1-19. [PMID: 40249667 DOI: 10.1080/17501911.2025.2491294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/31/2025] [Indexed: 04/20/2025] Open
Abstract
Genomic imprinting is an epigenetic phenomenon in mammals that affects brain development and behavior. Imprinting involves the regulation of allelic expression for some genes in offspring that depends on whether alleles are inherited from mothers compared to fathers, and is thought to provide parental control over offspring social behavior phenotypes. Imprinted gene expression is prevalent in the mammalian brain, and human imprinted gene mutations are associated with neurodevelopmental disorders and neurodivergent social behavior in Prader-Willi Syndrome, Angelman Syndrome, and autism. Here, we provide a review of the evidence that imprinted genes influence social behaviors across major neurodevelopmental stages in humans and mouse animal models that include parent-infant interactions, juvenile sociability, and adult aggression, dominance, and sexual behavior.
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Affiliation(s)
- Erin M O'Leary
- Neuroscience Program, University of Illinois, Urbana, IL, USA
| | - Paul J Bonthuis
- Neuroscience Program, University of Illinois, Urbana, IL, USA
- Department of Comparative Biosciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA
- Gene Networks in Neural & Development Plasticity Theme at Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL, USA
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Ballasy N, Apantaku I, Dean W, Hemberger M. Off to a good start: The importance of the placental exchange surface - Lessons from the mouse. Dev Biol 2025; 517:248-264. [PMID: 39491740 DOI: 10.1016/j.ydbio.2024.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/04/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
The role of the chorio-allantoic placenta as the critical nutrient- and oxygen-supplying organ to nourish the demands of the fetus has been well recognized. This function relies on the successful establishment of the placental feto-maternal exchange unit, or interhaemal barrier, across which all nutrients as well as waste products must pass to cross from the maternal to the fetal blood circulation, or vice versa, respectively. As a consequence, defects in the establishment of this elaborate interface lead to fetal growth retardation or even embryonic lethality, depending on the severity of the defect. Beyond this essential role, however, it has also emerged that the functionality of the feto-maternal interface dictates the proper development of specific embryonic organs, with tightest links observed to the formation of the heart. In this article, we build on the foundational strength of the mouse as experimental model in which the placental causality of embryonic defects can be genetically proven. We discuss in detail the formation of the interhaemal barrier that makes up the labyrinth layer of the murine placenta, including insights into drivers of its formation and the interdependence of the cell types that make up this essential interface, from in vivo and in vitro data using mouse trophoblast stem cells. We highlight mouse genetic tools that enable the elucidation of cause-effect relationships between defects driven by either the trophoblast cells of the placenta or by embryonic cell types. We specifically emphasize gene knockouts for which a placental causality of embryonic heart defects has been demonstrated. This in-depth perspective provides much-needed insights while highlighting remaining gaps in knowledge that are essential for gaining a better understanding of the multi-facetted roles of the placenta in setting us up for a healthy start in life well beyond nutritional support alone.
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Affiliation(s)
- Noura Ballasy
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Ifeoluwa Apantaku
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Wendy Dean
- Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Dept. of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
| | - Myriam Hemberger
- Dept. of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.
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3
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Hilman L, Ondičová M, Caffrey A, Clements M, Conway C, Ward M, Pentieva K, Irwin RE, McNulty H, Walsh CP. Cognitive benefits of folic acid supplementation during pregnancy track with epigenetic changes at an imprint regulator. BMC Med 2024; 22:579. [PMID: 39681839 PMCID: PMC11650848 DOI: 10.1186/s12916-024-03804-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/29/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND The human ZFP57 gene is a major regulator of imprinted genes, maintaining DNA methylation marks that distinguish parent-of-origin-specific alleles. DNA methylation of the gene itself has shown sensitivity to environmental stimuli, particularly folate status. However, the role of DNA methylation in ZFP57's own regulation has not been fully investigated. METHODS We used samples and data from our previously described randomised controlled trial (RCT) in pregnancy called Folic Acid Supplementation in the Second and Third Trimester (FASSTT), including follow-up of the children at age 11. Biometric and blood biochemistry results were examined for mothers and children. Methylation of ZFP57 was analysed by EPIC arrays, pyrosequencing and clonal analysis, and transcription assessed by PCR-based methods. Functional consequences of altered methylation were examined in cultured cells with mutations or by inhibition of the main DNA methyltransferases. DNA variants were examined using pyrosequencing and Sanger sequencing, with results compared to published studies using bioinformatic approaches. Cognitive outcomes were assessed using the Wechsler Intelligence Scale for Children 4th UK Edition (WISC-IV), with neural activity during language tasks quantified using magnetoencephalography (MEG). RESULTS Here we show that methylation at an alternative upstream promoter of ZFP57 is controlled in part by a quantitative trait locus (QTL). By altering DNA methylation levels, we demonstrate that this in turn controls the expression of the ZFP57 isoforms. Methylation at this region is also sensitive to folate levels, as we have previously shown in this cohort. Fully methylated alleles were associated with poorer performance in the Symbol Search and Cancellation subtests of WISC-IV in the children at age 11 years. There were also differences in neural activity during language tasks, as measured by MEG. Analysis of published genome-wide studies indicated other SNPs in linkage disequilibrium with the mQTL were also associated with neurodevelopmental outcomes. CONCLUSIONS While numbers in the current RCT were small and require further validation in larger cohorts, the results nevertheless suggest a molecular mechanism by which maternal folic acid supplementation during pregnancy may help to counteract the effects of folate depletion and positively influence cognitive development in the offspring.
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Affiliation(s)
- L Hilman
- School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - M Ondičová
- School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - A Caffrey
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - M Clements
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - C Conway
- School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - M Ward
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - K Pentieva
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - R E Irwin
- School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - H McNulty
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK
| | - C P Walsh
- School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK.
- Department for Cell and Neurobiology, Biomedical and Clinical Sciences Division, Faculty of Medicine, Linköping University, 581 83, Linköping, Sweden.
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Nair S, Khambata K, Warke H, Bansal V, Patil A, Ansari Z, Balasinor NH. Methylation aberrations in partner spermatozoa and impaired expression of imprinted genes in the placentae of early-onset preeclampsia. Placenta 2024; 158:275-284. [PMID: 39527857 DOI: 10.1016/j.placenta.2024.10.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/12/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Disturbed paternal epigenetic status of imprinted genes has been observed in infertility and recurrent spontaneous abortions. Shallow placentation has been associated with early-onset preeclampsia. Hence, the present study aimed to investigate the methylation patterns of imprinted genes involved in placental development, in the spermatozoa of partners of women experiencing preeclampsia. METHODS The study involved recruitment of couples into preeclampsia (n = 14) and control (n = 25) groups. Methylation analysis of imprinted gene differentially methylated regions (DMRs) and LINE1 repetitive element was carried out by pyrosequencing in the spermatozoa and placental villi. Global 5 mC levels in the spermatozoa were measured through ELISA. Expression of imprinted genes was quantified in the placental villi by real time qPCR. Association of birth weight with DNA methylation and gene expression was assessed. RESULTS KvDMR, PEG3 DMR, PEG10 DMR and DLK1-GTL2 IG-DMR were differentially methylated in the spermatozoa and placental villi of preeclampsia group. Global 5 mC content and LINE1 methylation levels did not differ between the spermatozoa of the two groups. Increased transcript levels of PEG3, IGF2, DLK1, PHLDA2 and CDKN1C were observed in the preeclamptic placental villi. Birth weight showed significant association with KvDMR, PEG10 DMR, DLK1-GTL2 IG-DMR and LINE1 methylation levels in the spermatozoa. DLK1 expression levels showed a negative association with birth weight. DISCUSSION The study highlighted the paternal contribution to early-onset preeclampsia, in the form of disrupted sperm DNA methylation patterns at imprinted gene loci. These loci, after further evaluation in future studies, could serve as sperm-based preeclampsia predictive markers, for couples planning pregnancy.
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Affiliation(s)
- Sweta Nair
- Department of Neuroendocrinology, National Institute for Research in Reproductive and Child Health, Mumbai, 400012, India
| | - Kushaan Khambata
- Department of Gamete Immunobiology, National Institute for Research in Reproductive and Child Health, Mumbai, 400012, India
| | - Himangi Warke
- Seth GS Medical College & KEM Hospital, Mumbai, 400012, India
| | - Vandana Bansal
- Nowrosjee Wadia Maternity Hospital, Mumbai, 400012, India
| | - Anushree Patil
- Department of Clinical Research, National Institute for Research in Reproductive and Child Health, Mumbai, 400012, India
| | - Zakiya Ansari
- Department of Neuroendocrinology, National Institute for Research in Reproductive and Child Health, Mumbai, 400012, India
| | - Nafisa H Balasinor
- Department of Neuroendocrinology, National Institute for Research in Reproductive and Child Health, Mumbai, 400012, India.
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Soliman HK, Coughlan JM. United by conflict: Convergent signatures of parental conflict in angiosperms and placental mammals. J Hered 2024; 115:625-642. [PMID: 38366852 PMCID: PMC11498613 DOI: 10.1093/jhered/esae009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/13/2024] [Indexed: 02/18/2024] Open
Abstract
Endosperm in angiosperms and placenta in eutherians are convergent innovations for efficient embryonic nutrient transfer. Despite advantages, this reproductive strategy incurs metabolic costs that maternal parents disproportionately shoulder, leading to potential inter-parental conflict over optimal offspring investment. Genomic imprinting-parent-of-origin-biased gene expression-is fundamental for endosperm and placenta development and has convergently evolved in angiosperms and mammals, in part, to resolve parental conflict. Here, we review the mechanisms of genomic imprinting in these taxa. Despite differences in the timing and spatial extent of imprinting, these taxa exhibit remarkable convergence in the molecular machinery and genes governing imprinting. We then assess the role of parental conflict in shaping evolution within angiosperms and eutherians using four criteria: 1) Do differences in the extent of sibling relatedness cause differences in the inferred strength of parental conflict? 2) Do reciprocal crosses between taxa with different inferred histories of parental conflict exhibit parent-of-origin growth effects? 3) Are these parent-of-origin growth effects caused by dosage-sensitive mechanisms and do these loci exhibit signals of positive selection? 4) Can normal development be restored by genomic perturbations that restore stoichiometric balance in the endosperm/placenta? Although we find evidence for all criteria in angiosperms and eutherians, suggesting that parental conflict may help shape their evolution, many questions remain. Additionally, myriad differences between the two taxa suggest that their respective biologies may shape how/when/where/to what extent parental conflict manifests. Lastly, we discuss outstanding questions, highlighting the power of comparative work in quantifying the role of parental conflict in evolution.
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Affiliation(s)
- Hagar K Soliman
- Department of Ecology & Evolutionary Biology, Yale University, New Haven, CT 06511, United States
- Department of Biotechnology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Jenn M Coughlan
- Department of Ecology & Evolutionary Biology, Yale University, New Haven, CT 06511, United States
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Anunciado-Koza RVP, Yin H, Bilodeau CL, Cooke D, Ables GP, Ryzhov S, Koza RA. Interindividual differences of dietary fat-inducible Mest in white adipose tissue of C57BL/6J mice are not heritable. Obesity (Silver Spring) 2024; 32:1144-1155. [PMID: 38616328 PMCID: PMC11132930 DOI: 10.1002/oby.24020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/01/2024] [Accepted: 02/20/2024] [Indexed: 04/16/2024]
Abstract
OBJECTIVE Differences in white adipose tissue (WAT) expression of mesoderm-specific transcript (Mest) in C57BL6/J mice fed a high-fat diet (HFD) are concomitant with and predictive for the development of obesity. However, the basis for differences in WAT Mest among mice is unknown. This study investigated whether HFD-inducible WAT Mest, as well as susceptibility to obesity, is transmissible from parents to offspring. METHODS WAT biopsies of mice fed an HFD for 2 weeks identified parents with low and high WAT Mest for breeding. Obesity phenotypes, WAT Mest, hepatic gene expression, and serum metabolites were determined in offspring fed an HFD for 2 weeks. RESULTS Offspring showed no heritability of obesity or WAT Mest phenotypes from parents but did show hepatic and serum metabolite changes consistent with their WAT Mest. Importantly, retired male breeders showed WAT Mest expression congruent with initial WAT biopsies even though HFD exposure occurred early in life. CONCLUSIONS Disparity of HFD-induced Mest in mice is not heritable but, rather, is reestablished during each generation and remains fixed from an early age to adulthood. Short-term HFD feeding reveals variation of WAT Mest expression within isogenic mice that is positively associated with the development of obesity.
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Affiliation(s)
| | - Haifeng Yin
- MaineHealth Institute for Research, Scarborough, Maine, USA
| | | | - Diana Cooke
- Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, New York, USA
| | - Gene P. Ables
- Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, New York, USA
| | - Sergey Ryzhov
- MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
- Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Robert A. Koza
- MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
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Simonenko SY, Bogdanova DA, Kuldyushev NA. Emerging Roles of Vitamin B 12 in Aging and Inflammation. Int J Mol Sci 2024; 25:5044. [PMID: 38732262 PMCID: PMC11084641 DOI: 10.3390/ijms25095044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Vitamin B12 (cobalamin) is an essential nutrient for humans and animals. Metabolically active forms of B12-methylcobalamin and 5-deoxyadenosylcobalamin are cofactors for the enzymes methionine synthase and mitochondrial methylmalonyl-CoA mutase. Malfunction of these enzymes due to a scarcity of vitamin B12 leads to disturbance of one-carbon metabolism and impaired mitochondrial function. A significant fraction of the population (up to 20%) is deficient in vitamin B12, with a higher rate of deficiency among elderly people. B12 deficiency is associated with numerous hallmarks of aging at the cellular and organismal levels. Cellular senescence is characterized by high levels of DNA damage by metabolic abnormalities, increased mitochondrial dysfunction, and disturbance of epigenetic regulation. B12 deficiency could be responsible for or play a crucial part in these disorders. In this review, we focus on a comprehensive analysis of molecular mechanisms through which vitamin B12 influences aging. We review new data about how deficiency in vitamin B12 may accelerate cellular aging. Despite indications that vitamin B12 has an important role in health and healthy aging, knowledge of the influence of vitamin B12 on aging is still limited and requires further research.
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Affiliation(s)
- Sergey Yu. Simonenko
- Research Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia;
| | - Daria A. Bogdanova
- Division of Immunobiology and Biomedicine, Center for Genetics and Life Sciences, Sirius University of Science and Technology, 354340 Sochi, Russia
| | - Nikita A. Kuldyushev
- Research Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia;
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Cevik SE, Skaar DA, Jima DD, Liu AJ, Østbye T, Whitson HE, Jirtle RL, Hoyo C, Planchart A. DNA methylation of imprint control regions associated with Alzheimer's disease in non-Hispanic Blacks and non-Hispanic Whites. Clin Epigenetics 2024; 16:58. [PMID: 38658973 PMCID: PMC11043040 DOI: 10.1186/s13148-024-01672-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 04/13/2024] [Indexed: 04/26/2024] Open
Abstract
Alzheimer's disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control regions (ICRs) is associated with AD. Differentially methylated regions (DMRs) were bioinformatically identified from whole-genome bisulfite sequenced DNA derived from brain tissue of 9 AD (5 NHBs and 4 NHWs) and 8 controls (4 NHBs and 4 NHWs). We identified DMRs located within 120 regions defined as candidate ICRs in the human imprintome ( https://genome.ucsc.edu/s/imprintome/hg38.AD.Brain_track ). Eighty-one ICRs were differentially methylated in NHB-AD, and 27 ICRs were differentially methylated in NHW-AD, with two regions common to both populations that are proximal to the inflammasome gene, NLRP1, and a known imprinted gene, MEST/MESTIT1. These findings indicate that early developmental alterations in DNA methylation of regions regulating genomic imprinting may contribute to AD risk and that this epigenetic risk differs between NHBs and NHWs.
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Affiliation(s)
- Sebnem E Cevik
- Toxicology Program, North Carolina State University, Raleigh, NC, USA
| | - David A Skaar
- Toxicology Program, North Carolina State University, Raleigh, NC, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
| | - Dereje D Jima
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
| | - Andy J Liu
- Department of Neurology, School of Medicine, Duke University, Durham, NC, USA
| | - Truls Østbye
- Department of Family Medicine and Community Health, Duke University, Durham, NC, USA
| | - Heather E Whitson
- Department of Medicine, School of Medicine, Duke University, Durham, NC, USA
- Duke Center for the Study of Aging and Human Development, Durham, NC, USA
- Duke/UNC Alzheimer's Disease Research Center (ADRC), Durham, NC, USA
| | - Randy L Jirtle
- Toxicology Program, North Carolina State University, Raleigh, NC, USA.
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA.
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
| | - Cathrine Hoyo
- Toxicology Program, North Carolina State University, Raleigh, NC, USA.
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA.
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA.
| | - Antonio Planchart
- Toxicology Program, North Carolina State University, Raleigh, NC, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA
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Tan JW, An JJ, Deane H, Xu H, Liao GY, Xu B. Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions. Mol Psychiatry 2024; 29:1192-1204. [PMID: 38212372 PMCID: PMC11176039 DOI: 10.1038/s41380-023-02404-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/13/2024]
Abstract
At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.
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Affiliation(s)
- Ji-Wei Tan
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, 33458, USA
| | - Juan Ji An
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, 33458, USA
| | - Hannah Deane
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, 33458, USA
- Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Haifei Xu
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, 33458, USA
| | - Guey-Ying Liao
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, 33458, USA
| | - Baoji Xu
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, University of Florida, Jupiter, FL, 33458, USA.
- Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, 33458, USA.
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10
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Ishihara T, Suzuki S, Newman TA, Fenelon JC, Griffith OW, Shaw G, Renfree MB. Marsupials have monoallelic MEST expression with a conserved antisense lncRNA but MEST is not imprinted. Heredity (Edinb) 2024; 132:5-17. [PMID: 37952041 PMCID: PMC10798977 DOI: 10.1038/s41437-023-00656-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 11/14/2023] Open
Abstract
The imprinted isoform of the Mest gene in mice is involved in key mammalian traits such as placental and fetal growth, maternal care and mammary gland maturation. The imprinted isoform has a distinct differentially methylated region (DMR) at its promoter in eutherian mammals but in marsupials, there are no differentially methylated CpG islands between the parental alleles. Here, we examined similarities and differences in the MEST gene locus across mammals using a marsupial, the tammar wallaby, a monotreme, the platypus, and a eutherian, the mouse, to investigate how imprinting of this gene evolved in mammals. By confirming the presence of the short isoform in all mammalian groups (which is imprinted in eutherians), this study suggests that an alternative promoter for the short isoform evolved at the MEST gene locus in the common ancestor of mammals. In the tammar, the short isoform of MEST shared the putative promoter CpG island with an antisense lncRNA previously identified in humans and an isoform of a neighbouring gene CEP41. The antisense lncRNA was expressed in tammar sperm, as seen in humans. This suggested that the conserved lncRNA might be important in the establishment of MEST imprinting in therian mammals, but it was not imprinted in the tammar. In contrast to previous studies, this study shows that MEST is not imprinted in marsupials. MEST imprinting in eutherians, therefore must have occurred after the marsupial-eutherian split with the acquisition of a key epigenetic imprinting control region, the differentially methylated CpG islands between the parental alleles.
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Affiliation(s)
- Teruhito Ishihara
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia
- Epigenetics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK
| | - Shunsuke Suzuki
- Department of Agricultural and Life Sciences, Shinshu University, Nagano, Japan
| | - Trent A Newman
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Jane C Fenelon
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Oliver W Griffith
- Department of Biological Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Geoff Shaw
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Marilyn B Renfree
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia.
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John RM, Higgs MJ, Isles AR. Imprinted genes and the manipulation of parenting in mammals. Nat Rev Genet 2023; 24:783-796. [PMID: 37714957 DOI: 10.1038/s41576-023-00644-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2023] [Indexed: 09/17/2023]
Abstract
Genomic imprinting refers to the parent-of-origin expression of genes, which originates from epigenetic events in the mammalian germ line. The evolution of imprinting may reflect a conflict over resource allocation early in life, with silencing of paternal genes in offspring soliciting increased maternal provision and silencing of maternal genes limiting demands on the mother. Parental caregiving has been identified as an area of potential conflict, with several imprinted genes serendipitously found to directly influence the quality of maternal care. Recent systems biology approaches, based on single-cell RNA sequencing data, support a more deliberate relationship, which is reinforced by the finding that imprinted genes expressed in the offspring influence the quality of maternal caregiving. These bidirectional, reiterative relationships between parents and their offspring are critical both for short-term survival and for lifelong wellbeing, with clear implications for human health.
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12
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Wang H, Cui X, Wang L, Fan N, Yu M, Qin H, Liu S, Yan Q. α1,3-fucosylation of MEST promotes invasion potential of cytotrophoblast cells by activating translation initiation. Cell Death Dis 2023; 14:651. [PMID: 37798282 PMCID: PMC10556033 DOI: 10.1038/s41419-023-06166-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 09/06/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023]
Abstract
Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo implantation, and dysfunction causes pregnancy failure. Protein glycosylation plays crucial roles in reproduction. However, it remains unclear whether the glycosylation of trophoblasts is involved in trophoblast migration and invasion processes during embryo implantation failure. By Lectin array, we discovered the decreased α1,3-fucosylation, especially difucosylated Lewis Y (LeY) glycan, in the villus tissues of miscarriage patients when compared with normal pregnancy women. Downregulating LeY biosynthesis by silencing the key enzyme fucosyltransferase IV (FUT4) inhibited migration and invasion ability of trophoblast cells. Using proteomics and translatomics, the specific LeY scaffolding glycoprotein of mesoderm-specific transcript (MEST) with glycosylation site at Asn163 was identified, and its expression enhanced migration and invasion ability of trophoblast cells. The results also provided novel evidence showing that decreased LeY modification on MEST hampered the binding of MEST with translation factor eIF4E2, and inhibited implantation-related gene translation initiation, which caused pregnancy failure. The α1,3-fucosylation of MEST by FUT4 may serve as a new biomarker for evaluating the functional state of pregnancy, and a target for infertility treatment.
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Affiliation(s)
- Hao Wang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China
| | - Xinyuan Cui
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China
| | - Luyao Wang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China
| | - Ningning Fan
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China
| | - Ming Yu
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China
| | - Huamin Qin
- Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, China
| | - Shuai Liu
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China.
| | - Qiu Yan
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China.
- Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian, 116044, China.
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Higgs MJ, Webberley AE, Allan AJ, Talat M, John RM, Isles AR. The parenting hub of the hypothalamus is a focus of imprinted gene action. PLoS Genet 2023; 19:e1010961. [PMID: 37856383 PMCID: PMC10586610 DOI: 10.1371/journal.pgen.1010961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/07/2023] [Indexed: 10/21/2023] Open
Abstract
Imprinted genes are subject to germline epigenetic modification resulting in parental-specific allelic silencing. Although genomic imprinting is thought to be important for maternal behaviour, this idea is based on serendipitous findings from a small number of imprinted genes. Here, we undertook an unbiased systems biology approach, taking advantage of the recent delineation of specific neuronal populations responsible for controlling parental care, to test whether imprinted genes significantly converge to regulate parenting behaviour. Using single-cell RNA sequencing datasets, we identified a specific enrichment of imprinted gene expression in a recognised "parenting hub", the galanin-expressing neurons of the preoptic area. We tested the validity of linking enriched expression in these neurons to function by focusing on MAGE family member L2 (Magel2), an imprinted gene not previously linked to parenting behaviour. We confirmed expression of Magel2 in the preoptic area galanin expressing neurons. We then examined the parenting behaviour of Magel2-null(+/p) mice. Magel2-null mothers, fathers and virgin females demonstrated deficits in pup retrieval, nest building and pup-directed motivation, identifying a central role for this gene in parenting. Finally, we show that Magel2-null mothers and fathers have a significant reduction in POA galanin expressing cells, which in turn contributes to a reduced c-Fos response in the POA upon exposure to pups. Our findings identify a novel imprinted gene that impacts parenting behaviour and, moreover, demonstrates the utility of using single-cell RNA sequencing data to predict gene function from expression and in doing so here, have identified a purposeful role for genomic imprinting in mediating parental behaviour.
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Affiliation(s)
- Matthew J. Higgs
- Behavioural Genetics Group, Centre for Neuropsychiatric, Genetics and Genomics, Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, United Kingdom
| | - Anna E. Webberley
- Behavioural Genetics Group, Centre for Neuropsychiatric, Genetics and Genomics, Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, United Kingdom
| | | | - Moaz Talat
- The Mary Lyon Centre, MRC Harwell, Didcot, United Kingdom
| | - Rosalind M. John
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Anthony R. Isles
- Behavioural Genetics Group, Centre for Neuropsychiatric, Genetics and Genomics, Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, United Kingdom
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14
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Sapehia D, Mahajan A, Singh P, Kaur J. High dietary folate and low vitamin B12 in parental diet disturbs the epigenetics of imprinted genes MEST and PHLDA2 in mice placenta. J Nutr Biochem 2023; 118:109354. [PMID: 37098363 DOI: 10.1016/j.jnutbio.2023.109354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 02/25/2023] [Accepted: 04/10/2023] [Indexed: 04/27/2023]
Abstract
To elucidate the dietary effects of vitamin B12 and folic acid on fetal and placental epigenetics, different dietary combinations of folic acid and low vitamin B12 (four groups) were fed to the animals (C57BL/6 mice), and mating was carried out within each group in the F0 generation. After weaning for 3 weeks in the F1 generation each group is divided into two sub-groups, while one group of mice was continued on the same diet (sustained group), the other was shifted to a normal diet (transient group) for 6-8 weeks (F1). Mating was carried out again within each group, and on day 20 of gestation, the maternal placenta (F1) and fetal tissues (F2) were isolated. Expression of imprinted genes and various epigenetic mechanisms, including global and gene-specific DNA methylation and post-translational histone modifications, were studied. Evaluation of mRNA levels of MEST and PHLDA2 in placental tissue revealed that their expression is maximally influenced by vitamin B12 deficiency and high folate conditions. The gene expression of MEST and PHLDA2 was found significantly decreased in the F0 generation, while over-expression was seen in BDFO dietary groups of F1 generation. These dietary combinations also resulted in DNA methylation changes in both generations, which may not play a role in gene expression regulation. However, altered histone modifications were found to be the major regulatory factor in controlling the expression of genes in the F1 generation. The imbalance of low vitamin B12 and high folate leads to increased levels of activating histone marks, contributing to increased gene expression.
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Affiliation(s)
- Divika Sapehia
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Aatish Mahajan
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Parampal Singh
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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15
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Sainty R, Silver MJ, Prentice AM, Monk D. The influence of early environment and micronutrient availability on developmental epigenetic programming: lessons from the placenta. Front Cell Dev Biol 2023; 11:1212199. [PMID: 37484911 PMCID: PMC10358779 DOI: 10.3389/fcell.2023.1212199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/27/2023] [Indexed: 07/25/2023] Open
Abstract
DNA methylation is the most commonly studied epigenetic mark in humans, as it is well recognised as a stable, heritable mark that can affect genome function and influence gene expression. Somatic DNA methylation patterns that can persist throughout life are established shortly after fertilisation when the majority of epigenetic marks, including DNA methylation, are erased from the pre-implantation embryo. Therefore, the period around conception is potentially critical for influencing DNA methylation, including methylation at imprinted alleles and metastable epialleles (MEs), loci where methylation varies between individuals but is correlated across tissues. Exposures before and during conception can affect pregnancy outcomes and health throughout life. Retrospective studies of the survivors of famines, such as those exposed to the Dutch Hunger Winter of 1944-45, have linked exposures around conception to later disease outcomes, some of which correlate with DNA methylation changes at certain genes. Animal models have shown more directly that DNA methylation can be affected by dietary supplements that act as cofactors in one-carbon metabolism, and in humans, methylation at birth has been associated with peri-conceptional micronutrient supplementation. However, directly showing a role of micronutrients in shaping the epigenome has proven difficult. Recently, the placenta, a tissue with a unique hypomethylated methylome, has been shown to possess great inter-individual variability, which we highlight as a promising target tissue for studying MEs and mixed environmental exposures. The placenta has a critical role shaping the health of the fetus. Placenta-associated pregnancy complications, such as preeclampsia and intrauterine growth restriction, are all associated with aberrant patterns of DNA methylation and expression which are only now being linked to disease risk later in life.
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Affiliation(s)
- Rebecca Sainty
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich, United Kingdom
| | - Matt J. Silver
- Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Andrew M. Prentice
- Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine, Banjul, Gambia
| | - David Monk
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich, United Kingdom
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16
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Kumar P, Courtes M, Lemmers C, Le Digarcher A, Coku I, Monteil A, Hong C, Varrault A, Liu R, Wang L, Bouschet T. Functional mapping of microRNA promoters with dCas9 fused to transcriptional regulators. Front Genet 2023; 14:1147222. [PMID: 37214422 PMCID: PMC10196145 DOI: 10.3389/fgene.2023.1147222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/18/2023] [Indexed: 05/24/2023] Open
Abstract
MicroRNAs are small non-coding RNAs that control gene expression during development, physiology, and disease. Transcription is a key factor in microRNA abundance and tissue-specific expression. Many databases predict the location of microRNA transcription start sites and promoters. However, these candidate regions require functional validation. Here, dCas9 fused to transcriptional activators or repressors - CRISPR activation (CRISPRa) and inhibition (CRISPRi)- were targeted to the candidate promoters of two intronic microRNAs, mmu-miR-335 and hsa-miR-3662, including the promoters of their respective host genes Mest and HBS1L. We report that in mouse embryonic stem cells and brain organoids, miR-335 was downregulated upon CRISPRi of its host gene Mest. Reciprocally, CRISPRa of Mest promoter upregulated miR-335. By contrast, CRISPRa of the predicted miR-335-specific promoter (located in an intron of Mest) did not affect miR-335 levels. Thus, the expression of miR-335 only depends on the promoter activity of its host gene Mest. By contrast, miR-3662 was CRISPR activatable both by the promoter of its host gene HBS1L and an intronic sequence in HEK-293T cells. Thus, CRISPRa and CRISPRi are powerful tools to evaluate the relevance of endogenous regulatory sequences involved in microRNA transcription in defined cell types.
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Affiliation(s)
- Pradeep Kumar
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Mathilde Courtes
- Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Céline Lemmers
- Plateforme de Vectorologie de Montpellier (PVM), BioCampus Montpellier, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Anne Le Digarcher
- Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Ilda Coku
- Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Arnaud Monteil
- Plateforme de Vectorologie de Montpellier (PVM), BioCampus Montpellier, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Charles Hong
- Vanderbilt University School of Medicine Nashville, Nashville, TN, United States
| | - Annie Varrault
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Runhua Liu
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Lizhong Wang
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Tristan Bouschet
- Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, Montpellier, France
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17
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Richard Albert J, Kobayashi T, Inoue A, Monteagudo-Sánchez A, Kumamoto S, Takashima T, Miura A, Oikawa M, Miura F, Takada S, Hirabayashi M, Korthauer K, Kurimoto K, Greenberg MVC, Lorincz M, Kobayashi H. Conservation and divergence of canonical and non-canonical imprinting in murids. Genome Biol 2023; 24:48. [PMID: 36918927 PMCID: PMC10012579 DOI: 10.1186/s13059-023-02869-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 02/09/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Genomic imprinting affects gene expression in a parent-of-origin manner and has a profound impact on complex traits including growth and behavior. 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 use low input methods for genome-wide analyses of gene expression and DNA methylation to profile embryonic and extraembryonic tissues at allele-specific resolution. RESULTS We identify 14 and 26 imprinted genes in these tissues, respectively, with 10 of these genes imprinted in both tissues. Comparative analyses with mouse reveal 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 extraembryonic 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 extraembryonic imprinting. Meta-analysis of novel imprinted genes reveals multiple mechanisms by which species-specific imprinted expression may be established, including H3K27me3 deposition in the oocyte, the appearance of ZFP57 binding motifs, and the insertion of endogenous retroviral promoters. CONCLUSIONS In summary, we provide an expanded 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.
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Affiliation(s)
| | - Toshihiro Kobayashi
- Division of Mammalian Embryology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Azusa Inoue
- YCI Laboratory for Metabolic Epigenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | | | - Soichiro Kumamoto
- NODAI Genome Research Center, Tokyo University of Agriculture, Tokyo, Japan
| | | | - Asuka Miura
- NODAI Genome Research Center, Tokyo University of Agriculture, Tokyo, Japan
| | - Mami Oikawa
- Division of Mammalian Embryology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Fumihito Miura
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Shuji Takada
- Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Masumi Hirabayashi
- Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Japan
| | - Keegan Korthauer
- Department of Statistics, University of British Columbia, Vancouver, Canada
- BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Kazuki Kurimoto
- Department of Embryology, Nara Medical University, Nara, Japan
| | | | - Matthew Lorincz
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
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Ryan NM, Heron EA. Evidence for parent-of-origin effects in autism spectrum disorder: a narrative review. J Appl Genet 2023; 64:303-317. [PMID: 36710277 PMCID: PMC10076404 DOI: 10.1007/s13353-022-00742-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/08/2022] [Accepted: 12/15/2022] [Indexed: 01/31/2023]
Abstract
Autism spectrum disorder (ASD) is a heterogeneous group of early-onset neurodevelopmental disorders known to be highly heritable with a complex genetic architecture. Abnormal brain developmental trajectories that impact synaptic functioning, excitation-inhibition balance and brain connectivity are now understood to play a central role in ASD. Ongoing efforts to identify the genetic underpinnings still prove challenging, in part due to phenotypic and genetic heterogeneity.This review focuses on parent-of-origin effects (POEs), where the phenotypic effect of an allele depends on its parental origin. POEs include genomic imprinting, transgenerational effects, mitochondrial DNA, sex chromosomes and mutational transmission bias. The motivation for investigating these mechanisms in ASD has been driven by their known impacts on early brain development and brain functioning, in particular for the most well-documented POE, genomic imprinting. Moreover, imprinting is implicated in syndromes such as Angelman and Prader-Willi, which frequently share comorbid symptoms with ASD. In addition to other regions in the genome, this comprehensive review highlights the 15q11-q13 and 7q chromosomal regions as well as the mitochondrial DNA as harbouring the majority of currently identified POEs in ASD.
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Affiliation(s)
- Niamh M Ryan
- Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
| | - Elizabeth A Heron
- Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
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Singh A, Pajni K, Panigrahi I, Khetarpal P. Clinical and Molecular Heterogeneity of Silver-Russell Syndrome and Therapeutic Challenges: A Systematic Review. Curr Pediatr Rev 2023; 19:157-168. [PMID: 35293298 DOI: 10.2174/1573396318666220315142542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/26/2021] [Accepted: 01/06/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Silver-Russell syndrome (SRS) is a developmental disorder involving extreme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic, and epigenetic mutations have been linked with SRS, the cause had only been identified in half of the cases. MATERIAL AND METHODS To have a better understanding of the SRS clinical presentation and mutation/ epimutation responsible for SRS, a systematic review of the literature was carried out using appropriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand the recurrence risk and the role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment, and management strategies of the affected patients through the analysis of selected literature. RESULTS 156 articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features was available for 228 patients only, and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at the 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases, and rarely, uniparental disomy of other autosomes (11, 14, 16, and 20 chromosomes) has been documented. Mutation in half of the cases is yet to be identified. Studies involving mice as experimental animals have been helpful in understanding the underlying molecular mechanism. As the clinical presentation of the syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort. CONCLUSION SRS is a clinically and genetically heterogeneous disorder, with most of the cases being implicated with a mutation in the 11p15 region and maternal disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with mice as a model organism have been useful in understanding the underlying molecular mechanism leading to the characteristic clinical presentation of the syndrome. Management strategies often need to be individualized due to varied clinical presentations.
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Affiliation(s)
- Amit Singh
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, 151401, India
| | - Ketan Pajni
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, 151401, India
| | - Inusha Panigrahi
- Department of Paediatric Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Preeti Khetarpal
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, 151401, India
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20
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Bruscadin JJ, Cardoso TF, da Silva Diniz WJ, Afonso J, de Souza MM, Petrini J, Nascimento Andrade BG, da Silva VH, Ferraz JBS, Zerlotini A, Mourão GB, Coutinho LL, de Almeida Regitano LC. Allele-specific expression reveals functional SNPs affecting muscle-related genes in bovine. BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - GENE REGULATORY MECHANISMS 2022; 1865:194886. [DOI: 10.1016/j.bbagrm.2022.194886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 09/27/2022] [Accepted: 10/12/2022] [Indexed: 11/09/2022]
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21
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Gan M, Ma J, Chen L, Zhang S, Niu L, Zhao Y, Li X, Pan H, Zhu L, Shen L. Identification of tRNA-derived small RNAs and their potential roles in porcine skeletal muscle with intrauterine growth restriction. Front Physiol 2022; 13:962278. [PMID: 36388094 PMCID: PMC9662792 DOI: 10.3389/fphys.2022.962278] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 10/10/2022] [Indexed: 07/30/2023] Open
Abstract
Intrauterine growth restriction (IUGR) in humans often manifests as poor growth and delayed intellectual development, whereas in domestic animals it results in increased mortality. As a novel epigenetic regulatory molecule, tRNA-derived small RNAs (tsRNAs) have been reported to be involved in many biological processes. In this study, pigs (35d) were used as a model to characterize tsRNAs by sequencing in normal and IUGR porcine skeletal muscle. A total of 586 tsRNAs were identified, of which 103 were specifically expressed in normal-size pigs and 38 were specifically expressed in IUGR pigs. The tsRNAs formed by splicing before the 5' end anti codon of mature tRNA (tRF-5c) accounted for over 90% of tsRNAs, which were significantly enriched in IUGR pigs than in normal-size pigs. Enriched pathways of differentially expressed tsRNAs target genes mainly included metabolic pathways, Rap1 signaling pathway, endocytosis, mTOR signaling pathway, and AMPK signaling pathway. Regulatory network analysis of target genes revealed that IGF1 was one of the most important molecules of regulatory nodes in IUGR and normal porcine skeletal muscle. In addition, IGF1 was found to be one of the target genes of tRF-Glu-TTC-047, which is a highly expressed tsRNA in IUGR pigs. The findings described herein uncover the role of tsRNAs in IUGR porcine skeletal muscle development, thus providing insights into the prevention and treatment of IUGR in mammals.
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Affiliation(s)
- Mailin Gan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Jianfeng Ma
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Lei Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Shunhua Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Lili Niu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Ye Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xuewei Li
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Hongmei Pan
- Key Laboratory of Pig Industry Science of Agriculture Ministry, Chongqing Academy of Animal Science, Chongqing, China
| | - Li Zhu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Linyuan Shen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China
- Farm Animal Genetic Resource Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
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Latchney SE, Cadney MD, Hopkins A, Garland T. DNA Methylation Analysis of Imprinted Genes in the Cortex and Hippocampus of Cross-Fostered Mice Selectively Bred for Increased Voluntary Wheel-Running. Behav Genet 2022; 52:281-297. [PMID: 35988119 PMCID: PMC9463359 DOI: 10.1007/s10519-022-10112-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/26/2022] [Indexed: 11/03/2022]
Abstract
We have previously shown that high runner (HR) mice (from a line genetically selected for increased wheel-running behavior) have distinct, genetically based, neurobiological phenotypes as compared with non-selected control (C) mice. However, developmental programming effects during early life, including maternal care and parent-of-origin-dependent expression of imprinted genes, can also contribute to variation in physical activity. Here, we used cross-fostering to address two questions. First, do HR mice have altered DNA methylation profiles of imprinted genes in the brain compared to C mice? Second, does maternal upbringing further modify the DNA methylation status of these imprinted genes? To address these questions, we cross-fostered all offspring at birth to create four experimental groups: C pups to other C dams, HR pups to other HR dams, C pups to HR dams, and HR pups to C dams. Bisulfite sequencing of 16 imprinted genes in the cortex and hippocampus revealed that the HR line had altered DNA methylation patterns of the paternally imprinted genes, Rasgrf1 and Zdbf2, as compared with the C line. Both fostering between the HR and C lines and sex modified the DNA methylation profiles for the paternally expressed genes Mest, Peg3, Igf2, Snrpn, and Impact. Ig-DMR, a gene with multiple paternal and maternal imprinted clusters, was also affected by maternal upbringing and sex. Our results suggest that differential methylation patterns of imprinted genes in the brain could contribute to evolutionary increases in wheel-running behavior and are also dependent on maternal upbringing and sex.
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Affiliation(s)
- Sarah E Latchney
- Department of Biology, St. Mary's College of Maryland, 18952 E. Fisher Rd, Saint Mary's City, MD, 20686, USA.
| | - Marcell D Cadney
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA, 92521, USA
| | | | - Theodore Garland
- Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA, 92521, USA
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23
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Ishihara T, Griffith OW, Suzuki S, Renfree MB. Placental imprinting of SLC22A3 in the IGF2R imprinted domain is conserved in therian mammals. Epigenetics Chromatin 2022; 15:32. [PMID: 36030241 PMCID: PMC9419357 DOI: 10.1186/s13072-022-00465-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/25/2022] [Indexed: 11/10/2022] Open
Abstract
Background The eutherian IGF2R imprinted domain is regulated by an antisense long non-coding RNA, Airn, which is expressed from a differentially methylated region (DMR) in mice. Airn silences two neighbouring genes, Solute carrier family 22 member 2 (Slc22a2) and Slc22a3, to establish the Igf2r imprinted domain in the mouse placenta. Marsupials also have an antisense non-coding RNA, ALID, expressed from a DMR, although the exact function of ALID is currently unknown. The eutherian IGF2R DMR is located in intron 2, while the marsupial IGF2R DMR is located in intron 12, but it is not yet known whether the adjacent genes SLC22A2 and/or SLC22A3 are also imprinted in the marsupial lineage. In this study, the imprinting status of marsupial SLC22A2 and SLC22A3 in the IGF2R imprinted domain in the chorio-vitelline placenta was examined in a marsupial, the tammar wallaby. Results In the tammar placenta, SLC22A3 but not SLC22A2 was imprinted. Tammar SLC22A3 imprinting was evident in placental tissues but not in the other tissues examined in this study. A putative promoter of SLC22A3 lacked DNA methylation, suggesting that this gene is not directly silenced by a DMR on its promoter as seen in the mouse. Based on immunofluorescence, we confirmed that the tammar SLC22A3 is localised in the endodermal cell layer of the tammar placenta where nutrient trafficking occurs. Conclusions Since SLC22A3 is imprinted in the tammar placenta, we conclude that this placental imprinting of SLC22A3 has been positively selected after the marsupial and eutherian split because of the differences in the DMR location. Since SLC22A3 is known to act as a transporter molecule for nutrient transfer in the eutherian placenta, we suggest it was strongly selected to control the balance between supply and demand of nutrients in marsupial as it does in eutherian placentas. Supplementary Information The online version contains supplementary material available at 10.1186/s13072-022-00465-4.
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Affiliation(s)
- Teruhito Ishihara
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Oliver W Griffith
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia.,Department of Biological Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Shunsuke Suzuki
- Department of Agricultural and Life Sciences, Faculty of Agriculture, Shinshu University, Nagano, 399-4598, Japan
| | - Marilyn B Renfree
- School of BioSciences, The University of Melbourne, Melbourne, VIC, 3010, Australia.
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24
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Anunciado-Koza RP, Stohn JP, Hernandez A, Koza RA. Social and maternal behavior in mesoderm specific transcript (Mest)-deficient mice. PLoS One 2022; 17:e0271913. [PMID: 35867696 PMCID: PMC9307168 DOI: 10.1371/journal.pone.0271913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 07/08/2022] [Indexed: 11/23/2022] Open
Abstract
Mesoderm specific transcript (Mest)/paternally expressed gene-1 (Peg1) is an imprinted gene expressed predominantly from the paternal allele. Aberrations in maternal behavior were previously reported in a Mest global knockout mouse (Mesttm1Masu). In this study, we performed in-depth social and maternal behavioral testing in a mouse model of Mest inactivation developed in our laboratory (Mesttm1.2Rkz). Mice with paternal allele inactivation (MestpKO) did not show anxiety after testing in the elevated plus maze, open field trial, and marble burying; nor depression-like behaviors in the tail suspension test. MestpKO showed normal social behaviors and memory/cognition in the three-chamber box test and the novel object recognition test, respectively. Primiparous MestpKO and MestgKO (biallelic Mest inactivation) female mice exhibited normal nest building and maternal behavior; and, virgin MestpKO and MestgKO female mice showed normal maternal instinct. Analyses of gene expression in adult hypothalamus, embryonic day 14.5 whole brain and adult whole brain demonstrated full abrogation of Mest mRNA in MestpKO and MestgKO mice with no effect on miR-335 expression. Our data indicates no discernible impairments in object recognition memory, social behavior or maternal behavior resulting from loss of Mest. The basis for the differences in maternal phenotypic behaviors between Mesttm1Masu and Mesttm1.2Rkz is not known.
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Affiliation(s)
- Rea P. Anunciado-Koza
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, United States of America
| | - J. Patrizia Stohn
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, United States of America
| | - Arturo Hernandez
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, United States of America
- Department of Medicine, Tufts University School of Medicine, Boston, MA, United States of America
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, United States of America
| | - Robert A. Koza
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, United States of America
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, United States of America
- Pennington Biomedical Research Center, Baton Rouge, LA, United States of America
- * E-mail:
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25
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Ku MS, Pan WC, Huang YT, Hsieh WS, Hsu YH, Chen PC, Liu CY. Associations between prenatal exposure to perfluoroalkyl substances, hypomethylation of MEST imprinted gene and birth outcomes. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 304:119183. [PMID: 35331797 DOI: 10.1016/j.envpol.2022.119183] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 06/14/2023]
Abstract
Prenatal perfluoroalkyl substance (PFAS) exposure has been linked to adverse birth outcomes, but the underlying mechanism has yet to be elucidated. DNA methylation changes in mesoderm-specific transcript (MEST) imprinted gene may be a mechanism of the prenatal exposure effects of PFASs on fetal growth. The aim was to investigate the prenatal PFASs exposure effects on DNA methylation changes in MEST imprinted gene involved in fetal growth. Among 486 mother-infant pairs from the Taiwan Birth Panel Study, PFASs and DNA methylation levels at 5 CpG sites of MEST promoter region were measured in cord blood. Univariable and multivariable linear regressions were performed to estimate the associations between prenatal PFAS exposure, MEST DNA methylation levels, and child birth outcomes. Mediation analysis was performed to examine the potential pathway of MEST methylation between PFASs and birth outcomes. We found that higher prenatal perfluorooctyl sulfonate (PFOS) exposure was significantly associated with lower methylation levels at 5 CpG sites of MEST promoter region (an adjusted β range: -1.56, -2.22). Significant negative associations were also found between MEST methylation levels and child birth weight. Furthermore, the associations between PFOS and perfluorooctanoic acid (PFOA) exposure and MEST methylation levels were more profound in girls than in boys. The mediated effect of average MEST methylation level between PFOS exposure and birth weight was 18.3 (95% CI = 2.1, 40.2; p = 0.014). The direct effect of PFOS exposure to birth weight independent to average MEST methylation level was -93.2 (95% CI = -170.5, -17.8; p = 0.018). In conclusion, our results suggest that prenatal PFAS exposure, especially PFOS, is associated with lower methylation levels at MEST promoter region, which not only leverages the role of imprinted gene in ensuring the integrity of fetal growth but also provides a potential mechanism for evaluating the prenatal exposure effect.
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Affiliation(s)
- Mei-Sheng Ku
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Wen-Chi Pan
- Institute of Environmental and Occupational Health Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Wu-Shiun Hsieh
- Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yi-Hsiang Hsu
- Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, 02131, USA; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA; Broad Institute of MIT and Harvard, Boston, MA, 02142, USA
| | - Pau-Chung Chen
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Chen-Yu Liu
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan.
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26
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Ishihara T, Hickford D, Fenelon JC, Griffith OW, Suzuki S, Renfree MB. Evolution of the short form of DNMT3A, DNMT3A2, occurred in the common ancestor of mammals. Genome Biol Evol 2022; 14:6615359. [PMID: 35749276 PMCID: PMC9254654 DOI: 10.1093/gbe/evac094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Genomic imprinting is found in marsupial and eutherian mammals, but not in monotremes. While the primary regulator of genomic imprinting in eutherians is differential DNA methylation between parental alleles, conserved imprinted genes in marsupials tend to lack DNA methylation at their promoters. DNA methylation at eutherian imprinted genes is mainly catalysed by a DNA methyltransferase (DNMT) enzyme, DNMT3A. There are two isoforms of eutherian DNMT3A: DNMT3A and DNMT3A2. DNMT3A2 is the primary isoform for establishing DNA methylation at eutherian imprinted genes and is essential for eutherian genomic imprinting. In this study, we investigated whether DNMT3A2 is also present in the two other mammalian lineages, marsupials and monotremes. We identified DNMT3A2 in both marsupials and monotremes, although imprinting has not been identified in monotremes. By analysing genomic sequences and transcriptome data across vertebrates, we concluded that the evolution of DNMT3A2 occurred in the common ancestor of mammals. In addition, DNMT3A/3A2 gene and protein expression during gametogenesis showed distinct sexual dimorphisms in a marsupial, the tammar wallaby, and this pattern coincided with the sex-specific DNA methylation reprogramming in this species as it does in mice. Our results show that DNMT3A2 is present in all mammalian groups and suggests that the basic DNMT3A/3A2-based DNA methylation mechanism is conserved at least in therian mammals.
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Affiliation(s)
- Teruhito Ishihara
- School of BioSciences, The University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Danielle Hickford
- School of BioSciences, The University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Jane C Fenelon
- School of BioSciences, The University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Oliver W Griffith
- Department of Biological Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Shunsuke Suzuki
- Department of Agricultural and Life Sciences, Shinshu University, Nagano, Japan
| | - Marilyn B Renfree
- School of BioSciences, The University of Melbourne, Melbourne, Victoria 3010, Australia
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27
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Mani S, Ghosh J, Rhon-Calderon EA, Lan Y, Ord T, Kalliora C, Chan J, Schultz B, Vaughan-Williams E, Coutifaris C, Sapienza C, Senapati S, Bartolomei MS, Mainigi M. Embryo cryopreservation leads to sex-specific DNA methylation perturbations in both human and mouse placentas. Hum Mol Genet 2022; 31:3855-3872. [PMID: 35717573 PMCID: PMC9652110 DOI: 10.1093/hmg/ddac138] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 12/25/2022] Open
Abstract
In vitro fertilization (IVF) is associated with DNA methylation abnormalities and a higher incidence of adverse pregnancy outcomes. However, which exposure(s), among the many IVF interventions, contributes to these outcomes remains unknown. Frozen embryo transfer (ET) is increasingly utilized as an alternative to fresh ET, but reports suggest a higher incidence of pre-eclampsia and large for gestational age infants. This study examines DNA methylation in human placentas using the 850K Infinium MethylationEPIC BeadChip array obtained after 65 programmed frozen ET cycles, 82 fresh ET cycles and 45 unassisted conceptions. Nine patients provided placentas following frozen and fresh ET from consecutive pregnancies for a paired subgroup analysis. In parallel, eight mouse placentas from fresh and frozen ET were analyzed using the Infinium Mouse Methylation BeadChip array. Human and mouse placentas were significantly hypermethylated after frozen ET compared with fresh. Paired analysis showed similar trends. Sex-specific analysis revealed that these changes were driven by male placentas in humans and mice. Frozen and fresh ET placentas were significantly different from controls, with frozen samples hypermethylated compared with controls driven by males and fresh samples being hypomethylated compared with controls, driven by females. Sexually dimorphic epigenetic changes could indicate differential susceptibility to IVF-associated perturbations, which highlights the importance of sex-specific evaluation of adverse outcomes. Similarities between changes in mice and humans underscore the suitability of the mouse model in evaluating how IVF impacts the epigenetic landscape, which is valuable given limited access to human tissue and the ability to isolate specific interventions in mice.
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Affiliation(s)
- Sneha Mani
- Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA,Center for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jayashri Ghosh
- Cancer and Cellular Biology, Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Eric A Rhon-Calderon
- Department of Cell and Developmental Biology, Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Yemin Lan
- Department of Cell and Developmental Biology, Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Teri Ord
- Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA,Center for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Charikleia Kalliora
- Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA,Center for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joe Chan
- Cancer and Cellular Biology, Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Bryant Schultz
- Cancer and Cellular Biology, Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Elaine Vaughan-Williams
- Cancer and Cellular Biology, Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Christos Coutifaris
- Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA,Center for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Carmen Sapienza
- Cancer and Cellular Biology, Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Suneeta Senapati
- Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA,Center for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marisa S Bartolomei
- Center for Research on Reproduction and Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA,Department of Cell and Developmental Biology, Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Monica Mainigi
- To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, 3701 Market Street, 8th floor, Philadelphia, PA 19104, USA. Tel: +1 2156622972; Fax: +1 2153495512;
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28
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Vincent KM, Stavropoulos DJ, Beaulieu-Bergeron M, Yang C, Jiang M, Zuijdwijk C, Dyment DA, Graham GE. A 79-kb paternally inherited 7q32.2 microdeletion involving MEST in a patient with a Silver-Russell syndrome-like phenotype. Am J Med Genet A 2022; 188:2421-2428. [PMID: 35593535 DOI: 10.1002/ajmg.a.62782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 04/05/2022] [Accepted: 04/14/2022] [Indexed: 11/07/2022]
Abstract
Maternal uniparental disomy of human chromosome 7 [upd(7)mat] is well-characterized as a cause of the growth disorder Silver-Russell syndrome (SRS). However, the causative gene is not currently known. There is growing evidence that molecular changes at the imprinted MEST region in 7q32.2 are associated with a phenotype evocative of SRS. This report details a patient with a SRS-like phenotype and a paternally inherited microdeletion of 79 kilobases (35-fold smaller than the previously reported smallest deletion) in the 7q32.2 region. This microdeletion encompasses only five genes, including MEST, which corroborates the hypothesis that MEST plays a central role in the 7q32.2 microdeletion growth disorder, as well as further implicating MEST in upd(7)mat SRS itself.
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Affiliation(s)
- Krista Marie Vincent
- Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.,Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dimitri J Stavropoulos
- Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
| | - Melanie Beaulieu-Bergeron
- Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.,Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Chen Yang
- Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.,Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Mary Jiang
- Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Caroline Zuijdwijk
- Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - David A Dyment
- Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.,Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Gail E Graham
- Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.,Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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29
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Genetic regulation and variation of expression of miRNA and mRNA transcripts in fetal muscle tissue in the context of sex, dam and variable fetal weight. Biol Sex Differ 2022; 13:24. [PMID: 35550009 PMCID: PMC9103043 DOI: 10.1186/s13293-022-00433-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/25/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Impaired skeletal muscle growth in utero can result in reduced birth weight and pathogenesis of intrauterine growth restriction. Fetal and placental growth is influenced by many factors including genetic, epigenetic and environmental factors. In fact, the sex and genotype of the fetus itself, as well as the mother providing it with a suitable environment, influence the growth of the fetus. Hence, our goal was to decipher and elucidate the molecular pathways of developmental processes mediated by miRNAs and mRNAs in fetal muscle tissue in the context of sex, dam, and fetal weight. Therefore, we analyse the variation of miRNA and mRNA expression in relation to these factors. In addition, the coincidence of genetic regulation of these mRNAs and miRNAs, as revealed by expression quantitative trait loci (eQTL) analyses, with sex-, mother- and weight-associated expression was investigated. METHODS A three-generation pig F2 population (n = 118) based on reciprocal crossing of German Landrace (DL) and Pietrain (Pi) was used. Genotype information and transcriptomic data (mRNA and miRNA) from longissimus dorsi muscle (LDM) of pig fetuses sampled at 63 days post-conception (dpc) were used for eQTL analyses. RESULTS The transcript abundances of 13, 853, and 275 probe-sets were influenced by sex, dam and fetal weight at 63 dpc, respectively (FDR < 5%). Most of significant transcripts affected by sex were located on the sex chromosomes including KDM6A and ANOS1 or autosomes including ANKS1B, LOC100155138 and miR-153. The fetal muscle transcripts associated with fetal weight indicated clearer metabolic directions than maternally influenced fetal muscle transcripts. Moreover, coincidence of genetic regulation (eQTL) and variation in transcript abundance due to sex, dam and fetal weight were identified. CONCLUSIONS Integrating information on eQTL, sex-, dam- and weight-associated differential expression and QTL for fetal weight allowed us to identify molecular pathways and shed light on the basic biological processes associated with differential muscle development in males and females, with implications for adaptive fetal programming.
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30
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Conflict and the evolution of viviparity in vertebrates. Behav Ecol Sociobiol 2022. [DOI: 10.1007/s00265-022-03171-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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31
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OUP accepted manuscript. Hum Reprod Update 2022; 28:629-655. [DOI: 10.1093/humupd/dmac010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/04/2022] [Indexed: 11/13/2022] Open
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32
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Dessì A, Tognazzi C, Bosco A, Pintus R, Fanos V. Metabolomic profiles and microbiota of GDM offspring: The key for future perspective? Front Pediatr 2022; 10:941800. [PMID: 36275053 PMCID: PMC9579340 DOI: 10.3389/fped.2022.941800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Gestational diabetes mellitus (GDM), or any degree of glucose intolerance recognized for the first time during pregnancy, is one of the diseases that most frequently aggravates the course of gestation. Missed or late diagnosis and inadequate treatment are associated with high maternal and fetal morbidity, with possible short- and long-term repercussions. Estimates on the prevalence of GDM are alarming and increasing by about 30% in the last 10-20 years. In addition, there is the negative influence of the SARS-CoV-2 emergency on the glycemic control of pregnant women, making the matter increasingly topical. To date, knowledge on the metabolic maturation of newborns is still incomplete. However, in light of the considerable progress of the theory of "developmental origins of health and disease," the relevant role of the intrauterine environment cannot be overlooked. In fact, due to the high plasticity of the early stages of development, some detrimental metabolic alterations during fetal growth, including maternal hyperglycemia, are associated with a higher incidence of chronic diseases in adult life. In this context, metabolomic analysis which allows to obtain a detailed phenotypic portrait through the dynamic detection of all metabolites in cells, tissues and different biological fluids could be very useful for the early diagnosis and prevention of complications. Indeed, if the diagnostic timing is optimized through the identification of specific metabolites, the detailed understanding of the altered metabolic pathway could also allow better management and more careful monitoring, also from a nutritional profile, of the more fragile children. In this context, a further contribution derives from the analysis of the intestinal microbiota, the main responsible for the fecal metabolome, given its alteration in pregnancies complicated by GDM and the possibility of transmission to offspring. The purpose of this review is to analyze the available data regarding the alterations in the metabolomic profile and microbiota of the offspring of mothers with GDM in order to highlight future prospects for reducing GDM-related complications in children of mothers affected by this disorder.
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Affiliation(s)
- Angelica Dessì
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Chiara Tognazzi
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Alice Bosco
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Roberta Pintus
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
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Prasad R, Jung H, Tan A, Song Y, Moon S, Shaker MR, Sun W, Lee J, Ryu H, Lim HK, Jho EH. Hypermethylation of Mest promoter causes aberrant Wnt signaling in patients with Alzheimer's disease. Sci Rep 2021; 11:20075. [PMID: 34625606 PMCID: PMC8501037 DOI: 10.1038/s41598-021-99562-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 09/28/2021] [Indexed: 02/08/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (Aβ) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD.
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Affiliation(s)
- Renuka Prasad
- Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea
| | - Hwajin Jung
- Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea
| | - Anderson Tan
- Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea
| | - Yonghee Song
- Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea
| | - Sungho Moon
- Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea
| | - Mohammed R Shaker
- Department of Anatomy, Korea University College of Medicine, Seoul, 02841, Republic of Korea
| | - Woong Sun
- Department of Anatomy, Korea University College of Medicine, Seoul, 02841, Republic of Korea
| | - Junghee Lee
- Boston University Alzheimer's Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Hoon Ryu
- Boston University Alzheimer's Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA, 02118, USA.
- Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
| | - Hyun Kook Lim
- Department of Psychiatry, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Eek-Hoon Jho
- Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea.
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Carollo A, Bonassi A, Lim M, Gabrieli G, Setoh P, Dimitriou D, Aryadoust V, Esposito G. Developmental disabilities across the world: A scientometric review from 1936 to 2020. RESEARCH IN DEVELOPMENTAL DISABILITIES 2021; 117:104031. [PMID: 34333315 DOI: 10.1016/j.ridd.2021.104031] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 06/07/2021] [Accepted: 07/12/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Developmental disabilities have been largely studied in the past years. Their etiological mechanisms have been underpinned to the interactions between genetic and environmental factors. These factors show variability across the world. Thus, it is important to understand where the set of knowledge obtained on developmental disabilities originates from and whether it is generalizable to low- and middle-income countries. AIMS This study aims to understand the origins of the available literature on developmental disabilities, keeping a focus on parenting, and identify the main trend of research. METHODS AND PROCEDURE A sample of 11,315 publications from 1936 to 2020 were collected from Scopus and a graphical country analysis was conducted. Furthermore, a qualitative approach enabled the clustering of references by keywords into four main areas: "Expression of the disorder", "Physiological Factors", "How it is studied" and "Environmental factors". For each area, a document co-citation analysis (DCA) on CiteSpace software was performed. OUTCOMES AND RESULTS Results highlight the leading role of North America in the study of developmental disabilities. Trends in the literature and the documents' scientific relevance are discussed in details. CONCLUSIONS AND IMPLICATIONS Results demand for investigation in different socio-economical settings to generalize our knowledge. What this paper adds? The current paper tries to provide insight into the origins of the literature on developmental disabilities with a focus on parenting, together with an analysis of the trends of research in the field. The paper consisted of a multi-disciplinary and multi-method review. In fact, the review tried to integrate the analysis of the relation between developmental disabilities with a closer look at the scientific contributions to the field across the world. Specifically, the paper integrates a total of 11,315 papers published on almost a century of research (from 1936 to 2020). An initial qualitative analysis on keywords was combined to a subsequent quantitative approach in order to maximize the comprehension of the impact of almost a century of scientific contributions. Specifically, documents were studied with temporal and structural metrics on a scientometric approach. This allowed the exploration of patterns within the literature available on Scopus in a quantitative way. This method not only assessed the importance of single documents within the network. As a matter of fact, the document co-citation analysis used on CiteSpace software provided insight into the relations existing between multiple documents in the field of research. As a result, the leading role of North America in the literature of developmental disabilities and parenting emerged. This was accompanied by the review of the main trends of research within the existing literature.
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Affiliation(s)
- Alessandro Carollo
- Department of Psychology and Cognitive Science, University of Trento, Rovereto, Italy
| | - Andrea Bonassi
- Department of Psychology and Cognitive Science, University of Trento, Rovereto, Italy; Mobile and Social Computing Lab, Bruno Kessler Foundation, Trento, Italy
| | - Mengyu Lim
- Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore, Singapore
| | - Giulio Gabrieli
- Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore, Singapore
| | - Peipei Setoh
- Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore, Singapore
| | - Dagmara Dimitriou
- Sleep Research and Education Laboratory, UCL Institute of Education, London, United Kingdom
| | - Vahid Aryadoust
- National Institute of Education, Nanyang Technological University, Singapore, Singapore
| | - Gianluca Esposito
- Department of Psychology and Cognitive Science, University of Trento, Rovereto, Italy; Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
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Cullen SM, Hassan N, Smith-Raska M. Effects of non-inherited ancestral genotypes on offspring phenotypes. Biol Reprod 2021; 105:747-760. [PMID: 34159361 DOI: 10.1093/biolre/ioab120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 11/13/2022] Open
Abstract
It is well established that environmental exposures can modify the profile of heritable factors in an individual's germ cells, ultimately affecting the inheritance of phenotypes in descendants. Similar to exposures, an ancestor's genotype can also affect the inheritance of phenotypes across generations, sometimes in offspring who do not inherit the genetic aberration. This can occur via a variety of prenatal, in utero, or postnatal mechanisms. In this review, we discuss the evidence for this process in mammals, with a focus on examples that are potentially mediated through the germline, while also considering alternate routes of inheritance. Non-inherited ancestral genotypes may influence descendant's disease risk to a much greater extent than currently appreciated, and focused evaluation of this phenomenon may reveal novel mechanisms of inheritance.
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Affiliation(s)
- Sean M Cullen
- Division of Newborn Medicine, Department of Pediatrics, Weill Cornell Medicine, 413 East 69th Street, Room 1252D, New York, NY 10021
| | - Nora Hassan
- Division of Newborn Medicine, Department of Pediatrics, Weill Cornell Medicine, 413 East 69th Street, Room 1252D, New York, NY 10021
| | - Matthew Smith-Raska
- Division of Newborn Medicine, Department of Pediatrics, Weill Cornell Medicine, 413 East 69th Street, Room 1252D, New York, NY 10021
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Suto JI, Kojima M. Low pup survival rate is associated with maternal Naq3 genotype and hypothalamic Vps8 expression levels in mice. Congenit Anom (Kyoto) 2021; 61:97-100. [PMID: 33289187 DOI: 10.1111/cga.12406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/25/2020] [Accepted: 12/01/2020] [Indexed: 11/29/2022]
Abstract
Pups born from females of the inbred mouse strain RR/Sgn tend to have low survival rates during rearing. We have previously identified Naq3, a quantitative trait locus underlying this low pup survival rate. In the present study, we confirmed the effect of Naq3 in congenic mice and investigated whether Vps8 is a candidate gene for Naq3. The survival rate of pups on the twelfth postpartum day was significantly decreased for mothers homozygous for the Naq3 allele. Hypothalamic expression of Vps8 was induced by nurturing in wild-type mice, and was significantly lower in Naq3 congenic mice than in wild-type mice. Thus, Vps8 is suggested to be involved in maternal nurturing, and therefore, as a plausible candidate gene for Naq3.
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Affiliation(s)
- Jun-Ichi Suto
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki, Japan
| | - Misaki Kojima
- Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki, Japan
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Ozmen A, Kipmen-Korgun D, Isenlik BS, Erman M, Sakinci M, Berkkanoglu M, Coetzee K, Ozgur K, Cetindag E, Yanar K, Korgun ET. Does fresh or frozen embryo transfer affect imprinted gene expressions in human term placenta? Acta Histochem 2021; 123:151694. [PMID: 33571695 DOI: 10.1016/j.acthis.2021.151694] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/26/2021] [Accepted: 01/28/2021] [Indexed: 11/28/2022]
Abstract
Our research aimed to compare the epigenetic alterations between placentae of in vitro fertilization (IVF) patients and spontaneous pregnancies. Additionally, the expression levels of proliferation markers (PCNA, Ki67) and glucose transporter proteins (GLUT1, GLUT3) were assessed in control and IVF placentae to examine the possible consequences of epigenetic alterations on placental development. Control group placentae were obtained from spontaneous pregnancies of healthy women (n = 16). IVF placentae were obtained from fresh (n = 16) and frozen (n = 16) embryo transfer pregnancies. A group of maternal and paternal imprint genes H19, IGF2, IGF2, IGF2R, PHLDA2, PLAGL1, MASH2, GRB10, PEG1, PEG3, and PEG10 were detected by Real-Time PCR. Additionally, PCNA, Ki67, GLUT1, and GLUT3 protein levels were assessed by immunohistochemistry and western blot. In the fresh embryo transfer placenta group (fETP), gene expression of paternal PEG1 and PEG10 was upregulated compared with the control group. Increased gene expression in paternal PEG1 and maternal IGFR2 genes was detected in the frozen embryo transfer placenta group (FET) compared with the control group. Conversely, expression levels of H19 and IGF2 genes were downregulated in the FET group. On the other hand, GLUT3 and PCNA expression was increased in FET group placentae. IVF techniques affect placental imprinted gene expressions which are important for proper placental development. Imprinted genes are differently expressed in fresh ET placentae and frozen ET placentae. In conclusion, these data indicate that altered imprinted gene expression may affect glucose transport and cell proliferation, therefore play an important role in placental development.
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Affiliation(s)
- Asli Ozmen
- Department of Histology and Embryology, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Dijle Kipmen-Korgun
- Department of Biochemistry, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Bekir Sitki Isenlik
- Department of Obstetrics and Gynecology, Training and Research Hospital, Health Sciences University, Antalya, Turkey
| | - Munire Erman
- Department of Obstetrics and Gynecology, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Mehmet Sakinci
- Department of Obstetrics and Gynecology, Medical Faculty, Akdeniz University, Antalya, Turkey
| | | | - Kevin Coetzee
- Antalya IVF, Halide Edip Cd. No:7, Kanal Mh., Antalya, Turkey
| | - Kemal Ozgur
- Antalya IVF, Halide Edip Cd. No:7, Kanal Mh., Antalya, Turkey
| | - Emre Cetindag
- Department of Histology and Embryology, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Kerem Yanar
- Department of Histology and Embryology, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Emin Turkay Korgun
- Department of Histology and Embryology, Medical Faculty, Akdeniz University, Antalya, Turkey.
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Kopca T, Tulay P. Association of Assisted Reproductive Technology Treatments with Imprinting Disorders. Glob Med Genet 2021; 8:1-6. [PMID: 33748817 PMCID: PMC7964251 DOI: 10.1055/s-0041-1723085] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Assisted reproductive technology (ART) is a broad field in infertility that encompasses different types of treatments. These revolutionary treatment methods aimed to aid infertile or subfertile couples. Treatment was expanded exponentially, as 1 to 3% of the births worldwide takes place with ART procedures. However, treatment is not flawless. Gametes and embryos are exposed to different chemicals and stress through treatment, which leads to disturbance in proper embryo development and results in prenatal and congenital anomalies. When compared with in-vivo development of gametes and preimplantation embryos in mice, in-vitro conditions during ART treatments have been suggested to disturb the gene expression levels, especially imprinted genes. Therefore, ART has been suggested to be associated with increased incidences of different imprinting disorders such as Beckwith–Wiedemann syndrome, Angelman syndrome, and Silver–Russell syndrome, as proved by different case reports and studies. This literature review aims to explain the association of imprinting disorders with this revolutionary treatment procedure.
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Affiliation(s)
- T Kopca
- Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus
| | - Pinar Tulay
- Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus.,Near East University, DESAM Institute, Nicosia, Cyprus
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Keshavarz M, Tautz D. The imprinted lncRNA Peg13 regulates sexual preference and the sex-specific brain transcriptome in mice. Proc Natl Acad Sci U S A 2021; 118:e2022172118. [PMID: 33658376 PMCID: PMC7958240 DOI: 10.1073/pnas.2022172118] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Mammalian genomes include many maternally and paternally imprinted genes. Most of these are also expressed in the brain, and several have been implicated in regulating specific behavioral traits. Here, we have used a knockout approach to study the function of Peg13, a gene that codes for a fast-evolving lncRNA (long noncoding RNA) and is part of a complex of imprinted genes on chromosome 15 in mice and chromosome 8 in humans. Mice lacking the 3' half of the transcript look morphologically wild-type but show distinct behavioral differences. They lose interest in the opposite sex, instead displaying a preference for wild-type animals of the same sex. Further, they show a higher level of anxiety, lowered activity and curiosity, and a deficiency in pup retrieval behavior. Brain RNA expression analysis reveals that genes involved in the serotonergic system, formation of glutamatergic synapses, olfactory processing, and estrogen signaling-as well as more than half of the other known imprinted genes-show significant expression changes in Peg13-deficient mice. Intriguingly, these pathways are differentially affected in the sexes, resulting in male and female brains of Peg13-deficient mice differing more from each other than those of wild-type mice. We conclude that Peg13 is part of a developmental pathway that regulates the neurobiology of social and sexual interactions.
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Affiliation(s)
- Maryam Keshavarz
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany
| | - Diethard Tautz
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany
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Chang S, Wang Y, Xin Y, Wang S, Luo Y, Wang L, Zhang H, Li J. DNA methylation abnormalities of imprinted genes in congenital heart disease: a pilot study. BMC Med Genomics 2021; 14:4. [PMID: 33407475 PMCID: PMC7789576 DOI: 10.1186/s12920-020-00848-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 12/03/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Congenital heart disease (CHD) is resulted from the interaction of genetic aberration and environmental factors. Imprinted genes, which are regulated by epigenetic modifications, are essential for the normal embryonic development. However, the role of imprinted genes in the etiology of CHD remains unclear. METHODS After the samples were treated with bisulfate salt, imprinted genes methylation were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. T test and One-way ANOVA were performed to evaluate the differences among groups. Odds ratios (ORs) were performed to evaluate the incidence risk of CHD in relation to methylation levels. RESULTS We investigated the alterations of imprinted gene germline differential methylation regions (gDMRs) methylation in patients with CHD. Eighteen imprinted genes that are known to affect early embryonic development were selected and the methylation modification genes were detected by massarray in 27 CHD children and 28 healthy children. Altered gDMR methylation level of 8 imprinted genes was found, including 2 imprinted genes with hypermethylation of GRB10 and MEST and 6 genes with hypomethylation of PEG10, NAP1L5, INPP5F, PLAGL1, NESP and MEG3. Stratified analysis showed that the methylation degree of imprinted genes was different in different types of CHD. Risk analysis showed that 6 imprinted genes, except MEST and NAP1L5, within a specific methylation level range were the risk factors for CHD CONCLUSION: Altered methylation of imprinted genes is associated with CHD and varies in different types of CHD. Further experiments are warranted to identify the methylation characteristics of imprinted genes in different types of CHD and clarify the etiologies of imprinted genes in CHD.
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Affiliation(s)
- Shaoyan Chang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Yubo Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Yu Xin
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Shuangxing Wang
- Department of Cardiac Surgery, Children's Hospital Affiliated to Capital Institute of Pediatrics, No. 2 Yabao Road, Chao Yang District, Beijing, 100020, China
| | - Yi Luo
- Department of Cardiac Surgery, Children's Hospital Affiliated to Capital Institute of Pediatrics, No. 2 Yabao Road, Chao Yang District, Beijing, 100020, China
| | - Li Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Hui Zhang
- Department of Cardiac Surgery, Children's Hospital Affiliated to Capital Institute of Pediatrics, No. 2 Yabao Road, Chao Yang District, Beijing, 100020, China.
| | - Jia Li
- Clinical Physiology Laboratory, Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, No. 9 Jinsui Road, Tianhe District, Guangzhou City, 510000, Guangdong Province, China.
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510000, Guangdong Province, China.
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Mota-Rojas D, Orihuela A, Strappini A, Villanueva-García D, Napolitano F, Mora-Medina P, Barrios-García HB, Herrera Y, Lavalle E, Martínez-Burnes J. Consumption of Maternal Placenta in Humans and Nonhuman Mammals: Beneficial and Adverse Effects. Animals (Basel) 2020; 10:E2398. [PMID: 33333890 PMCID: PMC7765311 DOI: 10.3390/ani10122398] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 11/16/2022] Open
Abstract
Placentophagia is a common mammalian behavior, and the first scientific study of the potential effects of human maternal placentophagia on lactation was in 1917. More recently, in the 1970s, human placentophagia was reported in North America with a trend toward increased consumption. There are different hypotheses about the women and nonhuman mammals' motivation towards placentophagia, but few have been subject to hypotheses testing. In women, the controversy continues; on the one hand, researchers attribute benefits like increased breast milk, weight gain in newborns, decreased postpartum depression and fatigue, and improved mothers' mood. In contrast, bacterial or viral infections, hormonal, or trace elements that could become toxic for both the mother and baby are reported as possible health risks. Other reports argue a lack of scientific rigor to support the self-reported benefits of placentophagia. Also, the way the placenta is prepared (raw, cooked, dehydrated, processed, or encapsulated) alters its components, and thus the desired effects. This review provides relevant information and the different hypotheses and points of view around placentophagia. However, there are still questions to be resolved, and more studies are needed to confirm or reject the data generated so far about placentophagia in humans and nonhuman mammals.
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Affiliation(s)
- Daniel Mota-Rojas
- Neurophysiology, Behavior and Animal Welfare Assessment, DPAA, Universidad Autónoma Metropolitana (UAM), 04960 Mexico City, Mexico; (D.M.-R.); (Y.H.); (E.L.)
| | - Agustín Orihuela
- Facultad de Ciencias Agropecuarias, Universidad Autónoma del Estado de Morelos, Cuernavaca, 62209 Morelos, Mexico;
| | - Ana Strappini
- Animal Science Institute, Faculty of Veterinary Sciences, Universidad Austral de Chile, 5110566 Valdivia, Chile;
| | - Dina Villanueva-García
- Division of Neonatology, National Institute of Health Hospital Infantil de México Federico Gómez, 06720 Mexico City, Mexico;
| | - Fabio Napolitano
- Scuola di Scienze Agrarie, Forestali, Alimentari ed Ambientali, Università degli Studi della Basilicata, 85100 Potenza, Italy;
| | - Patricia Mora-Medina
- Livestock Science Department, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México (UNAM), 54714 Mexico City, Mexico;
| | - Hugo B. Barrios-García
- Graduate and Research Department, Faculty of Veterinary Medicine, Universidad Autónoma de Tamaulipas, Ciudad Victoria, 87000 Tamaulipas, Mexico;
| | - Yuridia Herrera
- Neurophysiology, Behavior and Animal Welfare Assessment, DPAA, Universidad Autónoma Metropolitana (UAM), 04960 Mexico City, Mexico; (D.M.-R.); (Y.H.); (E.L.)
| | - Eunice Lavalle
- Neurophysiology, Behavior and Animal Welfare Assessment, DPAA, Universidad Autónoma Metropolitana (UAM), 04960 Mexico City, Mexico; (D.M.-R.); (Y.H.); (E.L.)
| | - Julio Martínez-Burnes
- Graduate and Research Department, Faculty of Veterinary Medicine, Universidad Autónoma de Tamaulipas, Ciudad Victoria, 87000 Tamaulipas, Mexico;
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Gurner KH, Truong TT, Harvey AJ, Gardner DK. A combination of growth factors and cytokines alter preimplantation mouse embryo development, foetal development and gene expression profiles. Mol Hum Reprod 2020; 26:953-970. [DOI: 10.1093/molehr/gaaa072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/29/2020] [Indexed: 12/15/2022] Open
Abstract
Abstract
Within the maternal tract, the preimplantation embryo is exposed to an array of growth factors (GFs) and cytokines, most of which are absent from culture media used in clinical IVF. Whilst the addition of individual GFs and cytokines to embryo culture media can improve preimplantation mouse embryo development, there is a lack of evidence on the combined synergistic effects of GFs and cytokines on embryo development and further foetal growth. Therefore, in this study, the effect of a combined group of GFs and cytokines on mouse preimplantation embryo development and subsequent foetal development and gene expression profiles was investigated. Supplementation of embryo culture media with an optimised combination of GFs and cytokines (0.05 ng/ml vascular endothelial GF, 1 ng/ml platelet-derived GF, 0.13 ng/ml insulin-like GF 1, 0.026 ng/ml insulin-like GF 2 and 1 ng/ml granulocyte colony-stimulating factor) had no effect on embryo morphokinetics but significantly increased trophectoderm cell number (P = 0.0002) and total cell number (P = 0.024). Treatment with this combination of GFs and cytokines also significantly increased blastocyst outgrowth area (P < 0.05) and, following embryo transfer, increased foetal weight (P = 0.027), crown-rump length (P = 0.017) and overall morphological development (P = 0.027). RNA-seq analysis of in vitro derived foetuses identified concurrent alterations to the transcriptional profiles of liver and placental tissues compared with those developed in vivo, with greater changes observed in the GF and cytokine treated group. Together these data highlight the importance of balancing the actions of such factors for the regulation of normal development and emphasise the need for further studies investigating this prior to clinical implementation.
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Affiliation(s)
- Kathryn H Gurner
- School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia
| | - Thi T Truong
- School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia
| | - Alexandra J Harvey
- School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia
| | - David K Gardner
- School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia
- Melbourne IVF, East Melbourne, VIC 3002, Australia
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Edwards CA, Takahashi N, Corish JA, Ferguson-Smith AC. The origins of genomic imprinting in mammals. Reprod Fertil Dev 2020; 31:1203-1218. [PMID: 30615843 DOI: 10.1071/rd18176] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 10/01/2018] [Indexed: 12/13/2022] Open
Abstract
Genomic imprinting is a process that causes genes to be expressed according to their parental origin. Imprinting appears to have evolved gradually in two of the three mammalian subclasses, with no imprinted genes yet identified in prototheria and only six found to be imprinted in marsupials to date. By interrogating the genomes of eutherian suborders, we determine that imprinting evolved at the majority of eutherian specific genes before the eutherian radiation. Theories considering the evolution of imprinting often relate to resource allocation and recently consider maternal-offspring interactions more generally, which, in marsupials, places a greater emphasis on lactation. In eutherians, the imprint memory is retained at least in part by zinc finger protein 57 (ZFP57), a Kruppel associated box (KRAB) zinc finger protein that binds specifically to methylated imprinting control regions. Some imprints are less dependent on ZFP57invivo and it may be no coincidence that these are the imprints that are found in marsupials. Because marsupials lack ZFP57, this suggests another more ancestral protein evolved to regulate imprints in non-eutherian subclasses, and contributes to imprinting control in eutherians. Hence, understanding the mechanisms acting at imprinting control regions across mammals has the potential to provide valuable insights into our understanding of the origins and evolution of genomic imprinting.
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Affiliation(s)
- Carol A Edwards
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
| | - Nozomi Takahashi
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
| | - Jennifer A Corish
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
| | - Anne C Ferguson-Smith
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
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Differences in Placental Imprinted Gene Expression across Preeclamptic and Non-Preeclamptic Pregnancies. Genes (Basel) 2020; 11:genes11101146. [PMID: 33003346 PMCID: PMC7601230 DOI: 10.3390/genes11101146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 11/16/2022] Open
Abstract
Preeclampsia is a multi-systemic syndrome that presents in approximately 5% of pregnancies worldwide and is associated with a range of subsequent postpartum and postnatal outcomes, including fetal growth restriction. As the placenta plays a critical role in the development of preeclampsia, surveying genomic features of the placenta, including expression of imprinted genes, may reveal molecular markers that can further refine subtypes to aid targeted disease management. In this study, we conducted a comprehensive survey of placental imprinted gene expression across early and late onset preeclampsia cases and preterm and term normotensive controls. Placentas were collected at delivery from women recruited at the Magee-Womens Hospital prenatal clinics, and expression levels were profiled across 109 imprinted genes. We observed downregulation of placental Mesoderm-specific transcript (MEST) and Necdin (NDN) gene expression levels (false discovery rate (FDR) < 0.05) among early onset preeclampsia cases compared to preterm controls. No differences in placental imprinted gene expression were observed between late onset preeclampsia cases and term controls. While few studies have linked NDN to pregnancy complications, reductions in MEST expression levels, as observed in our study, are consistently reported in the literature in relation to various pregnancy complications, including fetal growth restriction, suggesting a potential role for placental MEST expression as a biosensor of an adverse in utero environment.
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Sobral LM, Hicks HM, Parrish JK, McCann TS, Hsieh J, Goodspeed A, Costello JC, Black JC, Jedlicka P. KDM3A/Ets1 epigenetic axis contributes to PAX3/FOXO1-driven and independent disease-promoting gene expression in fusion-positive Rhabdomyosarcoma. Mol Oncol 2020; 14:2471-2486. [PMID: 32697014 PMCID: PMC7530783 DOI: 10.1002/1878-0261.12769] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/05/2020] [Accepted: 06/29/2020] [Indexed: 12/14/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. RMS exists as two major disease subtypes, oncofusion-negative RMS (FN-RMS) and oncofusion-positive RMS (FP-RMS). FP-RMS is characterized by recurrent PAX3/7-FOXO1 driver oncofusions and is a biologically and clinically aggressive disease. Recent studies have revealed FP-RMS to have a strong epigenetic basis. Epigenetic mechanisms represent potential new therapeutic vulnerabilities in FP-RMS, but their complex details remain to be defined. We previously identified a new disease-promoting epigenetic axis in RMS, involving the chromatin factor KDM3A and the Ets1 transcription factor. In the present study, we define the KDM3A and Ets1 FP-RMS transcriptomes and show that these interface with the recently characterized PAX3/FOXO1-driven gene expression program. KDM3A and Ets1 positively control numerous known and candidate novel PAX3/FOXO1-induced RMS-promoting genes, including subsets under control of PAX3/FOXO1-associated superenhancers (SE), such as MEST. Interestingly, KDM3A and Ets1 also positively control a number of known and candidate novel FP-RMS-promoting, but not PAX3/FOXO1-dependent, genes. Epistatically, Ets1 is downstream of, and exerts disease-promoting effects similar to, both KDM3A and PAX3/FOXO1. MEST also manifests disease-promoting properties in FP-RMS, and KDM3A and Ets1 each impacts activation of the PAX3/FOXO1-associated MEST SE. Taken together, our studies show that the KDM3A/Ets1 epigenetic axis plays an important role in disease promotion in FP-RMS, and provide insight into potential new ways to target aggressive phenotypes in this disease.
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Affiliation(s)
- Lays M Sobral
- Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Hannah M Hicks
- Cancer Biology Graduate Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Janet K Parrish
- Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Tyler S McCann
- Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Joseph Hsieh
- Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.,Cancer Biology Graduate Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.,Medical Scientist Training Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Andrew Goodspeed
- Department of Pharmacology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.,Bioinformatics Shared Resource, University of Colorado Cancer Center, Aurora, CO, USA
| | - James C Costello
- Department of Pharmacology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.,Bioinformatics Shared Resource, University of Colorado Cancer Center, Aurora, CO, USA
| | - Joshua C Black
- Department of Pharmacology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
| | - Paul Jedlicka
- Department of Pathology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.,Cancer Biology Graduate Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA.,Medical Scientist Training Program, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO, USA
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Chang S, Bartolomei MS. Modeling human epigenetic disorders in mice: Beckwith-Wiedemann syndrome and Silver-Russell syndrome. Dis Model Mech 2020; 13:dmm044123. [PMID: 32424032 PMCID: PMC7272347 DOI: 10.1242/dmm.044123] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Genomic imprinting, a phenomenon in which the two parental alleles are regulated differently, is observed in mammals, marsupials and a few other species, including seed-bearing plants. Dysregulation of genomic imprinting can cause developmental disorders such as Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). In this Review, we discuss (1) how various (epi)genetic lesions lead to the dysregulation of clinically relevant imprinted loci, and (2) how such perturbations may contribute to the developmental defects in BWS and SRS. Given that the regulatory mechanisms of most imprinted clusters are well conserved between mice and humans, numerous mouse models of BWS and SRS have been generated. These mouse models are key to understanding how mutations at imprinted loci result in pathological phenotypes in humans, although there are some limitations. This Review focuses on how the biological findings obtained from innovative mouse models explain the clinical features of BWS and SRS.
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Affiliation(s)
- Suhee Chang
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marisa S Bartolomei
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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47
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Chang S, Jing J, Shangguan S, Li B, Yao X, Liu X, Zhang T, Wu J, Wang L. The effect of folic acid deficiency on Mest/Peg1 in neural tube defects. Int J Neurosci 2020; 131:468-477. [PMID: 32241207 DOI: 10.1080/00207454.2020.1750386] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Neural tube defects (NTDs) are one of the most common and serious birth defects in human beings caused by genetic and environmental factors. Folate insufficiency is involved in the occurrence of NTDs and folic acid supplementation can prevent NTDs occurrence, however, the underlying mechanism remains poorly understood. METHODS We established cell and animal models of folic acid deficiency to detect the methylation modification and expression levels of genes by MassARRAY and real-time PCR, respectively. Results and conclusion: In the present study, we found firstly that in human folic acid-insufficient NTDs, the methylation level of imprinted gene Mest/Peg1 was decreased. By using a folic acid-deficient cell model, we demonstrated that Mest/Peg1 methylation was descended. Meanwhile, the mRNA level of Mest/Peg1 was up-regulated via hypomethylation modification under low folic acid conditions. Consistent with the results in cell models, Mest/Peg1 expression was elevated through hypomethylation regulation in folate-deficient animal models. Furthermore, the up-regulation of Mest/Peg1 inhibited the expression of Lrp6 gene, a crucial component of Wnt pathway. Similar results with Lrp6 down-regulation of fetal brain were verified in animal models under folic acid-deficient condition. Taken together, our findings indicated folic acid increased the expression of Mest/Peg1 via hypomethylation modification, and then inhibited Lrp6 expression, which may ultimately impact on the development of nervous system through the inactivation of Wnt pathway.
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Affiliation(s)
- Shaoyan Chang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Jia Jing
- Pediatrics Department, Qingdao Hiser Medical Group, Shandong Province, China
| | - Shaofang Shangguan
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Baiyi Li
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Xiuying Yao
- Department of Obstetrics and Gynecology, PLA Army General Hospital 263th Clinical Department, Beijing, China
| | - Xinli Liu
- Department of Obstetrics and Gynecology, PLA Army General Hospital 263th Clinical Department, Beijing, China
| | - Ting Zhang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Jianxin Wu
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Li Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
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48
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Johnson GL, Masias EJ, Lehoczky JA. Cellular Heterogeneity and Lineage Restriction during Mouse Digit Tip Regeneration at Single-Cell Resolution. Dev Cell 2020; 52:525-540.e5. [PMID: 32097654 PMCID: PMC7186907 DOI: 10.1016/j.devcel.2020.01.026] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 12/27/2022]
Abstract
Innate regeneration following digit tip amputation is one of the few examples of epimorphic regeneration in mammals. Digit tip regeneration is mediated by the blastema, the same structure invoked during limb regeneration in some lower vertebrates. By genetic lineage analyses, the digit tip blastema has been defined as a population of heterogeneous, lineage-restricted progenitor cells. These previous studies, however, do not comprehensively evaluate blastema heterogeneity or address lineage restriction of closely related cell types. In this report, we present single-cell RNA sequencing of over 38,000 cells from mouse digit tip blastemas and unamputated control digit tips and generate an atlas of the cell types participating in digit tip regeneration. We computationally define differentiation trajectories of vascular, monocytic, and fibroblastic lineages over regeneration, and while our data confirm broad lineage restriction of progenitors, our analysis reveals 67 genes enriched in blastema fibroblasts including a novel regeneration-specific gene, Mest.
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Affiliation(s)
- Gemma L Johnson
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Erick J Masias
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Jessica A Lehoczky
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
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49
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Wilkins JF, Bhattacharya T. Intragenomic conflict over bet-hedging. Philos Trans R Soc Lond B Biol Sci 2020; 374:20180142. [PMID: 30966914 DOI: 10.1098/rstb.2018.0142] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Genomic imprinting, where an allele's expression pattern depends on its parental origin, is thought to result primarily from an intragenomic evolutionary conflict. Imprinted genes are widely expressed in the brain and have been linked to various phenotypes, including behaviours related to risk tolerance. In this paper, we analyse a model of evolutionary bet-hedging in a system with imprinted gene expression. Previous analyses of bet-hedging have shown that natural selection may favour alleles and traits that reduce reproductive variance, even at the expense of reducing mean reproductive success, with the trade-off between mean and variance depending on the population size. In species where the sexes have different reproductive variances, this bet-hedging trade-off differs between maternally and paternally inherited alleles. Where males have the higher reproductive variance, alleles are more strongly selected to reduce variance when paternally inherited than when maternally inherited. We connect this result to phenotypes connected with specific imprinted genes, including delay discounting and social dominance. The empirical patterns are consistent with paternally expressed imprinted genes promoting risk-averse behaviours that reduce reproductive variance. Conversely, maternally expressed imprinted genes promote risk-tolerant, variance-increasing behaviours. We indicate how future research might further test the hypotheses suggested by our analysis. This article is part of the theme issue 'Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications'.
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Affiliation(s)
- Jon F Wilkins
- 1 Ronin Institute , Montclair, NJ 07043 , USA.,2 Santa Fe Institute , 1399 Hyde Park Road, Santa Fe, NM 87501 , USA
| | - Tanmoy Bhattacharya
- 2 Santa Fe Institute , 1399 Hyde Park Road, Santa Fe, NM 87501 , USA.,3 Group T2, Los Alamos National Laboratory , PO Box 1663, Los Alamos, NM 87545 , USA
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50
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Baines KJ, Rampersaud AM, Hillier DM, Jeyarajah MJ, Grafham GK, Eastabrook G, Lacefield JC, Renaud SJ. Antiviral Inflammation during Early Pregnancy Reduces Placental and Fetal Growth Trajectories. THE JOURNAL OF IMMUNOLOGY 2019; 204:694-706. [PMID: 31882516 DOI: 10.4049/jimmunol.1900888] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 11/28/2019] [Indexed: 12/22/2022]
Abstract
Many viruses are detrimental to pregnancy and negatively affect fetal growth and development. What is not well understood is how virus-induced inflammation impacts fetal-placental growth and developmental trajectories, particularly when inflammation occurs in early pregnancy during nascent placental and embryo development. To address this issue, we simulated a systemic virus exposure in early pregnant rats (gestational day 8.5) by administering the viral dsRNA mimic polyinosinic:polycytidylic acid (PolyI:C). Maternal exposure to PolyI:C induced a potent antiviral response and hypoxia in the early pregnant uterus, containing the primordial placenta and embryo. Maternal PolyI:C exposure was associated with decreased expression of the maternally imprinted genes Mest, Sfrp2, and Dlk1, which encode proteins critical for placental growth. Exposure of pregnant dams to PolyI:C during early pregnancy reduced fetal growth trajectories throughout gestation, concomitant with smaller placentas, and altered placental structure at midgestation. No detectable changes in placental hemodynamics were observed, as determined by ultrasound biomicroscopy. An antiviral response was not evident in rat trophoblast stem (TS) cells following exposure to PolyI:C, or to certain PolyI:C-induced cytokines including IL-6. However, TS cells expressed high levels of type I IFNR subunits (Ifnar1 and Ifnar2) and responded to IFN-⍺ by increasing expression of IFN-stimulated genes and decreasing expression of genes associated with the TS stem state, including Mest IFN-⍺ also impaired the differentiation capacity of TS cells. These results suggest that an antiviral inflammatory response in the conceptus during early pregnancy impacts TS cell developmental potential and causes latent placental development and reduced fetal growth.
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Affiliation(s)
- Kelly J Baines
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1
| | - Amanda M Rampersaud
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1
| | - Dendra M Hillier
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1
| | - Mariyan J Jeyarajah
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1
| | - Grace K Grafham
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1
| | - Genevieve Eastabrook
- Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, Canada N6H 5W9.,Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada N6C 2V5
| | - James C Lacefield
- Department of Electrical and Computer Engineering, School of Biomedical Engineering, University of Western Ontario, London, Ontario, Canada N6A 3K7.,Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada N6A 3K7; and.,Robarts Research Institute, University of Western Ontario, London, Ontario, Canada N6A 5B7
| | - Stephen J Renaud
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1; .,Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada N6C 2V5
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