24 research outputs found

    Phylogenetic and DNA methylation analysis reveal novel regions of variable methylation in the mouse IAP class of transposons

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    Abstract Background Select retrotransposons in the long terminal repeat (LTR) class exhibit interindividual variation in DNA methylation that is altered by developmental environmental exposures. Yet, neither the full extent of variability at these “metastable epialleles,” nor the phylogenetic relationship underlying variable elements is well understood. The murine metastable epialleles, Avy and CabpIAP, result from independent insertions of an intracisternal A particle (IAP) mobile element, and exhibit remarkably similar sequence identity (98.5%). Results Utilizing the C57BL/6 genome we identified 10802 IAP LTRs overall and a subset of 1388 in a family that includes Avy and CabpIAP. Phylogenetic analysis revealed two duplication and divergence events subdividing this family into three clades. To characterize interindividual variation across clades, liver DNA from 17 isogenic mice was subjected to combined bisulfite and restriction analysis (CoBRA) for 21 separate LTR transposons (7 per clade). The lowest and highest mean methylation values were 59% and 88% respectively, while methylation levels at individual LTRs varied widely, ranging from 9% to 34%. The clade with the most conserved elements had significantly higher mean methylation across LTRs than either of the two diverged clades (p = 0.040 and p = 0.017). Within each mouse, average methylation across all LTRs was not significantly different (71%-74%, p > 0.99). Conclusions Combined phylogenetic and DNA methylation analysis allows for the identification of novel regions of variable methylation. This approach increases the number of known metastable epialleles in the mouse, which can serve as biomarkers for environmental modifications to the epigenome.http://deepblue.lib.umich.edu/bitstream/2027.42/112312/1/12864_2012_Article_4665.pd

    The Effect of Developmental Iron Deficiency on Gene Expression, Tet Proteins, and Dna Hydroxymethylation In the Rodent Brain

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    University of Minnesota Ph.D. dissertation. June 2020. Major: Neuroscience. Advisor: Michael Georgieff. 1 computer file (PDF); 98 pages.Fetal-neonatal iron deficiency (ID) has a lasting negative impact on neurodevelopment, resulting in significant cognitive, socio-emotional, and learning and memory deficits in adulthood, as well as increased risk for neuropsychiatric disease. Given that ID is the most common micronutrient deficiency worldwide, and that pregnant women and young children are disproportionately affected, it presents a significant public health concern. Preclinical models have demonstrated that the developing central nervous system (CNS) is particularly affected by ID, and that the deleterious neurodevelopmental effects and neuropsychiatric risks that follow are associated with dysregulation of CNS gene expression. Dysregulated genes map to signaling pathways and networks critical for neurodevelopment and neuronal function, suggesting that these critical functions are compromised by ID. If developmental ID is corrected by iron repletion within a critical period, correction of neurodevelopmental deficits is possible. However, if iron repletion occurs outside of the critical period, the phenotypic and gene expression changes persist into adulthood despite correction of the deficiency. While changes in gene expression can be understood as the proximate cause of the ID neurocognitive phenotype, it is still unclear what the ultimate cause is. As such, there is a gap in our understanding of how developmental ID establishes and maintains gene expression changes in the CNS. A potential mechanism by which iron could enact these changes is through Ten-Eleven Translocation (TET) enzymes, a family of iron-dependent hydroxylases that generate the epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation. Epigenetic modifications such as DNA hydroxymethylation have the ability to stably influence gene expression throughout the lifespan, and are known to be labile to environmental influences. Of particular relevance, 5hmC is more abundant in the brain than any other tissue, and it increases in enrichment as neurodevelopment progresses, particularly in genes critical for neuronal development and function. The central hypothesis of my thesis research is that dysregulation of TET enzymatic activity and 5hmC by fetal-neonatal ID drives gene expression changes in brain that contribute to the long-term neurocognitive phenotype of developmental ID. To test this hypothesis, the following aims were proposed: 1) Determine the effect of fetal-neonatal ID on TET activity and 5hmC in two regions of the developing rat brain, the hippocampus and the cerebellum, and 2) Determine whether treatment of developmental ID with dietary iron repletion can reverse the changes to this epigenetic system. Completion of these aims contributes to the long-term goal of understanding the cellular and molecular underpinnings of CNS dysfunction and increased neuropsychiatric disease risk following developmental ID. Because the standard therapy of iron repletion incompletely rescues the neurodevelopmental phenotype of ID, there is a need for better therapeutic options. By better understanding the underlying mechanisms of ID-related hippocampal dysfunction, it may be possible to identify new therapeutic targets for more effective treatment of iron deficiency

    Early-Life Iron Deficiency Anemia Programs the Hippocampal Epigenomic Landscape

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    Iron deficiency (ID) anemia is the foremost micronutrient deficiency worldwide, affecting around 40% of pregnant women and young children. ID during the prenatal and early postnatal periods has a pronounced effect on neurodevelopment, resulting in long-term effects such as cognitive impairment and increased risk for neuropsychiatric disorders. Treatment of ID has been complicated as it does not always resolve the long-lasting neurodevelopmental deficits. In animal models, developmental ID results in abnormal hippocampal structure and function associated with dysregulation of genes involved in neurotransmission and synaptic plasticity. Dysregulation of these genes is a likely proximate cause of the life-long deficits that follow developmental ID. However, a direct functional link between iron and gene dysregulation has yet to be elucidated. Iron-dependent epigenetic modifications are one mechanism by which ID could alter gene expression across the lifespan. The jumonji and AT-rich interaction domain-containing (JARID) protein and the Ten-Eleven Translocation (TET) proteins are two families of iron-dependent epigenetic modifiers that play critical roles during neural development by establishing proper gene regulation during critical periods of brain development. Therefore, JARIDs and TETs can contribute to the iron-mediated epigenetic mechanisms by which early-life ID directly causes stable changes in gene regulation across the life span

    Early-Life Iron Deficiency Anemia Programs the Hippocampal Epigenomic Landscape

    No full text
    Iron deficiency (ID) anemia is the foremost micronutrient deficiency worldwide, affecting around 40% of pregnant women and young children. ID during the prenatal and early postnatal periods has a pronounced effect on neurodevelopment, resulting in long-term effects such as cognitive impairment and increased risk for neuropsychiatric disorders. Treatment of ID has been complicated as it does not always resolve the long-lasting neurodevelopmental deficits. In animal models, developmental ID results in abnormal hippocampal structure and function associated with dysregulation of genes involved in neurotransmission and synaptic plasticity. Dysregulation of these genes is a likely proximate cause of the life-long deficits that follow developmental ID. However, a direct functional link between iron and gene dysregulation has yet to be elucidated. Iron-dependent epigenetic modifications are one mechanism by which ID could alter gene expression across the lifespan. The jumonji and AT-rich interaction domain-containing (JARID) protein and the Ten-Eleven Translocation (TET) proteins are two families of iron-dependent epigenetic modifiers that play critical roles during neural development by establishing proper gene regulation during critical periods of brain development. Therefore, JARIDs and TETs can contribute to the iron-mediated epigenetic mechanisms by which early-life ID directly causes stable changes in gene regulation across the life span

    Prenatal Iron Deficiency and Choline Supplementation Interact to Epigenetically Regulate Jarid1b and Bdnf in the Rat Hippocampus into Adulthood

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    Early-life iron deficiency (ID) causes long-term neurocognitive impairments and gene dysregulation that can be partially mitigated by prenatal choline supplementation. The long-term gene dysregulation is hypothesized to underlie cognitive dysfunction. However, mechanisms by which iron and choline mediate long-term gene dysregulation remain unknown. In the present study, using a well-established rat model of fetal-neonatal ID, we demonstrated that ID downregulated hippocampal expression of the gene encoding JmjC-ARID domain-containing protein 1B (JARID1B), an iron-dependent histone H3K4 demethylase, associated with a higher histone deacetylase 1 (HDAC1) enrichment and a lower enrichment of acetylated histone H3K9 (H3K9ac) and phosphorylated cAMP response element-binding protein (pCREB). Likewise, ID reduced transcriptional capacity of the gene encoding brain-derived neurotrophic factor (BDNF), a target of JARID1B, associated with repressive histone modifications such as lower H3K9ac and pCREB enrichments at the Bdnf promoters in the adult rat hippocampus. Prenatal choline supplementation did not prevent the ID-induced chromatin modifications at these loci but induced long-lasting repressive chromatin modifications in the iron-sufficient adult rats. Collectively, these findings demonstrated that the iron-dependent epigenetic mechanism mediated by JARID1B accounted for long-term Bdnf dysregulation by early-life ID. Choline supplementation utilized a separate mechanism to rescue the effect of ID on neural gene regulation. The negative epigenetic effects of choline supplementation in the iron-sufficient rat hippocampus necessitate additional investigations prior to its use as an adjunctive therapeutic agent

    Weekly Weights Data

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    This file contains weekly weight data (g) for mice used in this study
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