Browsing by Subject "CpG Islands"
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Item Open Access Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm.(Epigenetics, 2020-01) Schrott, Rose; Acharya, Kelly; Itchon-Ramos, Nilda; Hawkey, Andrew B; Pippen, Erica; Mitchell, John T; Kollins, Scott H; Levin, Edward D; Murphy, Susan KParental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.Item Open Access Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort.(Epigenetics, 2014-08) Hoyo, Cathrine; Daltveit, Anne Kjersti; Iversen, Edwin; Benjamin-Neelon, Sara E; Fuemmeler, Bernard; Schildkraut, Joellen; Murtha, Amy P; Overcash, Francine; Vidal, Adriana C; Wang, Frances; Huang, Zhiqing; Kurtzberg, Joanne; Seewaldt, Victoria; Forman, Michele; Jirtle, Randy L; Murphy, Susan KEpigenetic mechanisms are proposed to link maternal concentrations of methyl group donor nutrients with the risk of low birth weight. However, empirical data are lacking. We have examined the association between maternal folate and birth weight and assessed the mediating role of DNA methylation at nine differentially methylated regions (DMRs) of genomically imprinted genes in these associations. Compared with newborns of women with folate levels in the lowest quartile, birth weight was higher in newborns of mothers in the second (β = 143.2, se = 63.2, P = 0.02), third (β = 117.3, se = 64.0, P = 0.07), and fourth (β = 133.9, se = 65.2, P = 0.04) quartiles, consistent with a threshold effect. This pattern of association did not vary by race/ethnicity but was more apparent in newborns of non-obese women. DNA methylation at the PLAGL1, SGCE, DLK1/MEG3 and IGF2/H19 DMRs was associated with maternal folate levels and also birth weight, suggestive of threshold effects. MEG3 DMR methylation mediated the association between maternal folate levels and birth weight (P =0.06). While the small sample size and partial scope of examined DMRs limit our conclusions, our data suggest that, with respect to birth weight, no additional benefits may be derived from increased maternal folate concentrations, especially in non-obese women. These data also support epigenetic plasticity as a key mechanistic response to folate availability during early fetal development.Item Open Access Sperm DNA methylation altered by THC and nicotine: Vulnerability of neurodevelopmental genes with bivalent chromatin.(Scientific reports, 2020-09) Schrott, Rose; Rajavel, Maya; Acharya, Kelly; Huang, Zhiqing; Acharya, Chaitanya; Hawkey, Andrew; Pippen, Erica; Lyerly, H Kim; Levin, Edward D; Murphy, Susan KMen consume the most nicotine and cannabis products but impacts on sperm epigenetics are poorly characterized. Evidence suggests that preconception exposure to these drugs alters offspring neurodevelopment. Epigenetics may in part facilitate heritability. We therefore compared effects of exposure to tetrahydrocannabinol (THC) and nicotine on DNA methylation in rat sperm at genes involved in neurodevelopment. Reduced representation bisulfite sequencing data from sperm of rats exposed to THC via oral gavage showed that seven neurodevelopmentally active genes were significantly differentially methylated versus controls. Pyrosequencing data revealed majority overlap in differential methylation in sperm from rats exposed to THC via injection as well as those exposed to nicotine. Neurodevelopmental genes including autism candidates are vulnerable to environmental exposures and common features may mediate this vulnerability. We discovered that autism candidate genes are significantly enriched for bivalent chromatin structure, suggesting this configuration may increase vulnerability of genes in sperm to disrupted methylation.Item Open Access Telomere-to-telomere assembly of a complete human X chromosome.(Nature, 2020-09) Miga, Karen H; Koren, Sergey; Rhie, Arang; Vollger, Mitchell R; Gershman, Ariel; Bzikadze, Andrey; Brooks, Shelise; Howe, Edmund; Porubsky, David; Logsdon, Glennis A; Schneider, Valerie A; Potapova, Tamara; Wood, Jonathan; Chow, William; Armstrong, Joel; Fredrickson, Jeanne; Pak, Evgenia; Tigyi, Kristof; Kremitzki, Milinn; Markovic, Christopher; Maduro, Valerie; Dutra, Amalia; Bouffard, Gerard G; Chang, Alexander M; Hansen, Nancy F; Wilfert, Amy B; Thibaud-Nissen, Françoise; Schmitt, Anthony D; Belton, Jon-Matthew; Selvaraj, Siddarth; Dennis, Megan Y; Soto, Daniela C; Sahasrabudhe, Ruta; Kaya, Gulhan; Quick, Josh; Loman, Nicholas J; Holmes, Nadine; Loose, Matthew; Surti, Urvashi; Risques, Rosa Ana; Graves Lindsay, Tina A; Fulton, Robert; Hall, Ira; Paten, Benedict; Howe, Kerstin; Timp, Winston; Young, Alice; Mullikin, James C; Pevzner, Pavel A; Gerton, Jennifer L; Sullivan, Beth A; Eichler, Evan E; Phillippy, Adam MAfter two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.