Browsing by Author "Resendiz, Marisol"

Now showing 1 - 5 of 5
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    Cell-Wide DNA De-Methylation and Re-Methylation of Purkinje Neurons in the Developing Cerebellum
    (Plos, 2016-09) Zhou, Feng C.; Resendiz, Marisol; Lo, Chiao-Ling; Chen, Yuanyuan; Department of Anatomy & Cell Biology, IU School of Medicine
    Global DNA de-methylation is thought to occur only during pre-implantation and gametogenesis in mammals. Scalable, cell-wide de-methylation has not been demonstrated beyond totipotent stages. Here, we observed a large scale de-methylation and subsequent re-methylation (CDR) (including 5-methylcytosine (5mC) and 5-hydroxylmethylcytosine (5hmC)) in post-mitotic cerebellar Purkinje cells (PC) through the course of normal development. Through single cell immuno-identification and cell-specific quantitative methylation assays, we demonstrate that the CDR event is an intrinsically scheduled program, occurring in nearly every PC. Meanwhile, cerebellar granule cells and basket interneurons adopt their own DNA methylation program, independent of PCs. DNA de-methylation was further demonstrated at the gene level, on genes pertinent to PC development. The PC, being one of the largest neurons in the brain, may showcase an amplified epigenetic cycle which may mediate stage transformation including cell cycle arrest, vast axonal-dendritic growth, and synaptogenesis at the onset of neuronal specificity. This discovery is a key step toward better understanding the breadth and role of DNA methylation and de-methylation during neural ontology.
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    DNA Methylation program in normal and alcohol-induced thinning cortex
    (Elsevier, 2017-05) Öztürk, Nail Can; Resendiz, Marisol; Öztürk, Hakan; Zhou, Feng C.; Anatomy and Cell Biology, School of Medicine
    While cerebral underdevelopment is a hallmark of fetal alcohol spectrum disorders (FASD), the mechanism(s) guiding the broad cortical neurodevelopmental deficits are not clear. DNA methylation is known to regulate early development and tissue specification through gene regulation. Here, we examined DNA methylation in the onset of alcohol-induced cortical thinning in a mouse model of FASD. C57BL/6 (B6) mice were administered a 4% alcohol (v/v) liquid diet from embryonic (E) days 7–16, and their embryos were harvested at E17, along with isocaloric liquid diet and lab chow controls. Cortical neuroanatomy, neural phenotypes, and epigenetic markers of methylation were assessed using immunohistochemistry, Western blot, and methyl-DNA assays. We report that cortical thickness, neuroepithelial proliferation, and neuronal migration and maturity were found to be deterred by alcohol at E17. Simultaneously, DNA methylation, including 5-methylcytosine (5mC) and 5-hydroxcylmethylcytosine (5hmC), which progresses as an intrinsic program guiding normal embryonic cortical development, was severely affected by in utero alcohol exposure. The intricate relationship between cortical thinning and this DNA methylation program disruption is detailed and illustrated. DNA methylation, dynamic across the multiple cortical layers during the late embryonic stage, is highly disrupted by fetal alcohol exposure; this disruption occurs in tandem with characteristic developmental abnormalities, ranging from structural to molecular. Finally, our findings point to a significant question for future exploration: whether epigenetics guides neurodevelopment or whether developmental conditions dictate epigenetic dynamics in the context of alcohol-induced cortical teratogenesis.
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    Epigenetic medicine and fetal alcohol spectrum disorders
    (Taylor & Francis, 2013) Resendiz, Marisol; Chen, Yuanyuan; Öztürk, Nail C.; Zhou, Feng C.; Anatomy, Cell Biology and Physiology, School of Medicine
    Epigenetic medicine is still in its infancy. To date, only a handful of diseases have documented epigenetic correlates upstream of gene regulation including cancer, developmental syndromes and late-onset diseases. The finding that epigenetic markers are dynamic and heterogeneous at tissue and cellular levels, combined with recent identification of a new form of functionally distinct DNA methylation has opened a wider window for investigators to pry into the epigenetic world. It is anticipated that many diseases will be elucidated through this epigenetic inquiry. In this review, we discuss the normal course of DNA methylation during development, taking alcohol as a demonstrator of the epigenetic impact of environmental factors in disease etiology, particularly the growth retardation and neurodevelopmental deficits of fetal alcohol spectrum disorders.
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    Epigenetic regulation of the neural transcriptome and alcohol interference during development
    (Frontiers Media, 2014-08-26) Resendiz, Marisol; Mason, Stephen; Lo, Chiao-Ling; Zhou, Feng C.; Anatomy, Cell Biology and Physiology, School of Medicine
    Alcohol intoxicated cells broadly alter their metabolites - among them methyl and acetic acid can alter the DNA and histone epigenetic codes. Together with the promiscuous effect of alcohol on enzyme activities (including DNA methyltransferases) and the downstream effect on microRNA and transposable elements, alcohol is well placed to affect intrinsic transcriptional programs of developing cells. Considering that the developmental consequences of early alcohol exposure so profoundly affect neural systems, it is not unfounded to reason that alcohol exploits transcriptional regulators to challenge canonical gene expression and in effect, intrinsic developmental pathways to achieve widespread damage in the developing nervous system. To fully evaluate the role of epigenetic regulation in alcohol-related developmental disease, it is important to first gather the targets of epigenetic players in neurodevelopmental models. Here, we attempt to review the cellular and genomic windows of opportunity for alcohol to act on intrinsic neurodevelopmental programs. We also discuss some established targets of fetal alcohol exposure and propose pathways for future study. Overall, this review hopes to illustrate the known epigenetic program and its alterations in normal neural stem cell development and further, aims to depict how alcohol, through neuroepigenetics, may lead to neurodevelopmental deficits observed in fetal alcohol spectrum disorders.
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    The regulatory role and environmental sensitivity of DNA methylation in neurodevelopment
    (2017-06-01) Resendiz, Marisol; Zhou, Feng
    The emerging field of epigenetics is expanding our understanding of how biological diversity is generated in the face of genetic limitations. One epigenetic mechanism in particular, DNA methylation, has demonstrated a dynamic range during neural development. Here, we provide evidence that DNA methylation occurs as a cell unique program aiding in the regulation of neurodevelopmental gene expression. DNA methylation has demonstrated sensitivity to external inputs ranging from stress to chemical exposure and dietary factors. To explore DNA methylation as a means of communicating early-life stress to the brain, we utilized a mouse model of fetal alcohol spectrum disorders (FASD). FASD presents a range of neurodevelopmental deficits and is a leading cause of neurodevelopmental disabilities in the United States. Predicated on the knowledge of alcohol's teratogenic role in brain development, we describe that the normal pattern of cortical DNA methylation and epigenetic correlates is similarly impacted by prenatal alcohol exposure. Due to the biochemical interaction of alcohol metabolism and the pathways regulating DNA methylation synthesis, we further investigated whether dietary manipulation could normalize the cortical DNA methylation program and aid in the protection of FASD characteristics. We found that the alcohol sensitive DNA methylation landscape is dually capable of registering dietary intervention, demonstrating normalization of disease-related patterns in the cortex and improved neurodevelopmental gene expression and morphology. Finally, we investigated the DNA methylation landscape in a crucial corticodevelopmental gene to more accurately define the breadth and scope of the environmental impacts at the nucleotide level. We found that alcohol and dietary supplementation are selective for regions associated with transcriptional control. Collectively, the evidence supports that DNA methylation plays a regulatory role in development and that its sensitivity to external inputs is dynamic and detectable at the smallest genomic level. Importantly, DNA methylation landscapes are adaptable and thus bear diagnostic and therapeutic potential.