Biology subjects

Neier, K. E.

Publications and source records attributed to Neier, K. E..

5 recordsLinked to original sources

bioRxiv2025

Female cortical cellular mosaicism underlies shared MeCP2 and PCB impacted gene pathways

Etiologies of neurodevelopmental disorders involve genes and environment however their interactions are understudied. Rett Syndrome (RTT) is an X-linked, dominant neurodevelopmental disorder caused by mutations in MECP2, encoding the epigenetic regulator methyl CpG binding protein. Epigenetic features of MECP2 expression due to X-linked cellular mosaicism and the variability in severity and timing of progression in RTT suggest interaction with environmental neurotoxicants such as lipophilic polychlorinated biphenyls (PCBs). To understand shared mechanisms, we exposed WT and Mecp2e1-/+ female mice to a human-relevant PCB mixture and dose, then performed single-nucleus 5 RNA-seq from cortex. We identified significant overlap in dysregulated genes and 71 shared pathways between the effects of PCB exposure and MeCP2 mutation, and co-mitigation of their transcriptional impacts. PCBs influenced the non-cell- autonomous transcriptional effects of MeCP2 mutations in wild-type-expressing neurons within the mosaic mutant female cortex in both mouse and human, suggesting that the interactions predominantly involve homeostatic gene networks.

systems biology↗

bioRxiv2025

Light and sex modify Snord116 genotype effects on metabolism, behavior, and imprinted gene networks following circadian entrainment

Mammals utilize imprinted and X-linked epigenetic mechanisms in development, metabolism, and behavior. Imprinted genes, including Prader-Willi syndrome Snord116 noncoding RNAs, are implicated in the regulation of sleep and circadian rhythms through poorly understood mechanisms. Utilizing mouse models of Snord116 deficiency and overexpression, we performed an integrated, sex-stratified analysis of free running behaviors, indirect calorimetry, and cortical transcriptomes following entrainment to a 22 hour light:dark T-cycle. We observed significant interactions of sex, entrainment, and Snord116 genotype in period length at baseline and after-effects of post-entrainment. Snord116 deletions effect on respiratory exchange ratio was light sensitive, with sex and entrainment effects dominant under total darkness. Snord116 genotype impacted both rhythmic and non-rhythmic cortical gene networks that integrated sex, light, and entrainment effects with genotype-phenotype correlations. A co-expressed gene network enriched for imprinted, Snord116-target, and Xist-proximal long noncoding RNAs was identified as a light-sensitive regulatory hub of sexual dimorphic responses to a dynamic environment.

animal behavior and cognition↗

bioRxiv2023

The role of intestine in metabolic dysregulation in murine Wilson disease

Background and aimsMajor clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, and little is known about other tissues involvement in metabolic changes in WD. In vitro studies suggested that the loss of intestinal ATP7B could contribute to metabolic dysregulation in WD. We tested this hypothesis by evaluating gut microbiota and lipidome in two mouse models of WD and by characterizing a new mouse model with a targeted deletion of Atp7b in intestine. MethodsCecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and the Atp7b null global knockout mouse models of WD were profiled and integrated. Intestine-specific Atp7b knockout mice (Atp7b{Delta}IEC) was generated using B6.Cg-Tg(Vil1-cre)997Gum/J mice and Atp7bLox/Lox mice, and characterized using targeted lipidome analysis following a high-fat diet challenge. ResultsGut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated tri- and diglyceride, phospholipid, and sphingolipid metabolism in WD models. When challenged with a high-fat diet, Atp7b{Delta}IEC mice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells. ConclusionCoordinated changes of gut microbiome and lipidome analyses underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence phenotypic presentations.

molecular biology↗

bioRxiv2021

Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

BackgroundPolychlorinated biphenyls (PCBs) are developmental neurotoxicants implicated as environmental risk factors for neurodevelopmental disorders (NDD), including autism spectrum disorders (ASD). ObjectiveWe examined the effects of prenatal exposure to a human-relevant mixture of PCBs on the DNA methylome of fetal mouse brain and placenta to determine if there was a shared subset of differentially methylated regions (DMRs). MethodsA PCB mixture formulated to model the 12 most abundant congeners detected in the serum of pregnant women from a prospective high-risk ASD cohort was administered to female mice prior to and during pregnancy. Whole-genome bisulfite sequencing (WGBS) was performed to assess genome-wide DNA methylation profiles of placenta and brain on gestational day 18. ResultsWe found thousands of significant (empirical p < 0.05) DMRs distinguishing placentas and brains from PCB-exposed embryos from sex-matched vehicle controls. In both placenta and brain, PCB-associated DMRs were significantly (p < 0.005) enriched for functions related to neurodevelopment, cellular adhesion, and cellular signaling, and significantly (Odds Ratio > 2.4, q < 0.003) enriched for bivalent chromatin marks. The placenta and brain PCB DMRs overlapped significantly (Z-score = 4.5, p = 0.0001) by genomic coordinate and mapped to a shared subset of genes significantly (q < 0.05) enriched for Wnt signaling, Slit/Robo signaling, and genes differentially expressed in multiple NDD/ASD models. The placenta and brain DMRs also significantly (q < 0.05) overlapped by genomic coordinate with brain samples from humans with Rett syndrome and Dup15q syndrome. DiscussionThese results demonstrate that placenta can be used as a surrogate for embryonic brain DNA methylation changes over genes relevant to NDD/ASD in a mouse model of prenatal PCB exposure.

genomics↗

bioRxiv2019

Perinatal exposure to lead results in altered DNA methylation in adult mouse liver and blood: Implications for target versus surrogate tissue use in environmental epigenetics

BackgroundDNA methylation is a critical epigenetic mechanism linking early developmental environment to long-term health. In humans, the extent to which toxicant-induced changes in DNA methylation in surrogate tissues, such as blood, mirror those in the target tissues is unclear. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues.\n\nObjectivesThe objective of this study was to investigate the effects of perinatal exposure to a human environmentally relevant level (32 ppm in maternal drinking water) of lead (Pb) on liver and blood DNA methylation in adult male and female mice. We hypothesized that developmental Pb exposure would lead to persistent changes in DNA methylation, and that a subset of differentially methylated loci would overlap between liver and blood.\n\nMethodsEnhanced reduced-representation bisulfite sequencing was used to assess DNA methylation in 5 month old Pb-exposed and control mice. Sex-stratified modeling of differential methylation by Pb exposure was conducted using an established bioinformatics pipeline.\n\nResultsAlthough Pb exposure ceased at 3 weeks of age, we observed thousands of stably modified, sex-specific differentially methylated regions in the blood and liver of Pb-exposed animals, including 44 genomically imprinted loci. In males, we discovered 5 sites that overlapped between blood and liver, and exhibited changes in DNA methylation in the same direction in both tissues.\n\nConclusionsThese data demonstrate that perinatal exposure to Pb induces sex-specific changes in hepatic DNA methylation in adulthood, some of which are also present in blood. Ongoing studies will provide additional exposure-specific insights, and include other epigenetic marks that will enable further refinement of the design and analysis of human studies where target tissues are inaccessible.

genomics↗