2016 — 2020 |
Xie, Hehuang |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Epigenetic Role of Egr1 During Postnatal Brain Development and in Neuronal Activity @ Virginia Polytechnic Inst and St Univ
TITLE: The epigenetic role of EGR1 during postnatal brain development and in neuronal activity Project Summary/Abstract Early growth response gene-1 (Egr1) is a critical transcription factor involved in many important biological processes, including neuronal plasticity and memory formation. With a rapid increase in expression during the first few weeks after birth, Egr1 controls the selection, maturation and functional integration of newborn neurons. The regulation of Egr1-mediated gene expression has been shown to be under methylation control. However, Egr1 target sites and their epigenetic regulation in the nervous system remains largely unknown. The investigators have recently identified a large number of genomic loci with their cell-type specific methylation patterns established during postnatal frontal cortex development. For both human and mouse, these loci enrich for transcription factor binding motifs, in particular for Egr1. The CpG dinucleotides within these predicted EGR1 binding sites become hypo-methylated in mature neurons but remain heavily methylated in glia. In this study, the investigators propose to systematically investigate Egr1-mediated epigenetic regulatory networks underlying the postnatal brain development. The central hypothesis is that, Egr1 is a key mediator for gene-environment interactions shaping brain methylome during early postnatal development, and plays an essential role in the establishment of cell-type specific DNA methylation patterns and in the epigenetic control of activity-induced methylation changes. In Aim 1, the investigators will determine the methylation profiles of EGR1 binding sites during postnatal brain development. In Aim 2, the investigators will determine DNA demethylation mechanism underlying the postnatal brain development. Gain- or loss-of-function methods will be used to manipulate Egr1 and Tet enzymes expression to test the hypothesis that increased Egr1 and Tet enzymes expression is prerequisites for the establishment of the cell-type specifically methylation patterns on its target sites during development. In addition, the investigators will examine whether high basal Egr1 expression is required to maintain the hypo-methylation states of its binding sites. Given the critical role of Egr1 in brain development and function, the investigators anticipate that these studies will provide important new insights into the key epigenetic mechanisms that underlie postnatal brain development and neuronal activity.
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0.904 |
2020 |
Jarome, Timothy Joseph (co-PI) [⬀] Xie, Hehuang |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Exploring Epigenetic Regulation of Memory Extinction @ Virginia Polytechnic Inst and St Univ
TITLE: EXPLORING EPIGENETIC REGULATION OF MEMORY EXTINCTION PROJECT SUMMARY The broad goal of this proposal is to understand how fear memories are extinguished in the brain. Extinction learning, in which continued exposure to cues associated with an aversive event result in reduced responding to these cues, has been proposed as a way to modify or erase fear memories. However, the molecular mechanisms that control the extinction process remain poorly defined, limiting the therapeutic potential of this behavioral process. Recent evidence suggests that extinction learning requires the functions of neuronal activity induced transcription factors including EGR1 and DNA demethylation enzyme TET1 in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DHPC), though it is unknown how these two mechanisms regulate the extinction process. Our recent study indicated that EGR1 recruits TET1 to remove methylation marks on brain DNA during early postnatal development, though whether such a relationship exists during learning-dependent synaptic plasticity in the adult brain remains equivocal. The purpose of this grant is to explore how these two proteins interact to control memory extinction processes with two specific aims. In Aim 1, the investigators will determine the epigenetic roles of EGR1 and TET1 in the mPFC and DHPC during the extinction of fear memory using a combination of behavioral paradigms in genetic knockout mouse models with whole-genome next generation sequencing approaches. In Aim 2, using targeted CRISPR-dCas9 manipulations in the mPFC and DHPC, the investigators will determine the epigenetic role of EGR1-dependent recruitment of TET1 to the memory permissive gene Npas4 during memory extinction. Collectively, the success of this project will provide novel insights into our understanding of the epigenetic role of Egr1/Tet1 and Npas4 genes during extinction consolidation and significantly broaden our understanding of the mechanisms underlying memory extinction, which could potentially lead to new treatment therapeutic strategies for the treatment fear memories associated with a variety of psychiatric disorders.
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0.904 |
2020 — 2021 |
Wang, Xiaobin (co-PI) [⬀] Xie, Hehuang |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Functional Rna Modifications, Micronutrient Exposure, Developmental Disabilities @ Virginia Polytechnic Inst and St Univ
TITLE: FUNCTIONAL RNA MODIFICATIONS, MICRONUTRIENT EXPOSURE, DEVELOPMENTAL DISABILITIES PROJECT SUMMARY This proposal will combine the strengths of experimental mouse model with human prospective birth cohort study and transdisciplinary expertise to test novel hypotheses that functional RNA methylation (coupled with DNA methylation) may be one of the mechanisms underlying the association between maternal folate status and child risk of autism spectrum disorders (ASD). The role of maternal folate status in child risk of ASD has received great attention and is in debate. While many studies suggest beneficial effect of higher maternal folate intake against autism, a few studies raised concern about the potential harm of high prenatal folate intake. In the Boston Birth Cohort (BBC), PI's group demonstrated a wide variation of maternal folate levels, ranging from insufficiency to excess, which is consistent with the finding in NHANES, a U.S. nationally representative sample. A `U shaped' relationship was found between frequency of maternal multivitamin supplementation and ASD risk; this association was further supported by the findings based on measured maternal plasma folate levels. Furthermore, the preliminary data from PI's group suggest that maternal folate intake may have an impact on RNA methylation metabolism. Two specific aims were proposed: Aim1 will determine folate-associated alterations in RNA methylation and RNA/DNA methylation dynamics using mouse neural stem cells (NSCs). RNA/DNA methylation profiles will be determined using transcriptome-wide and genome-wide bisulfite sequencing, protein translation will be determined using polysome profiling, and folate-associated alterations in NSC proliferation and differentiation will be characterized. In-utero folate exposure-associated RNA/DNA methylation alterations will be determined using a mouse model. Aim 2 will determine RNA methylation sites associated with in-utero folate exposure in cord blood samples. The inter-relationship of prenatal folate status, RNA/DNA methylation, and child risk of ASD will be determined via the integration of individual clinical features with corresponding RNA methylation and DNA methylation information. This proposed study, if successful, will provide new insight on how environmental exposures (here folate is used as an example) are involved in the functional activities of RNA modifications and RNA/DNA methylation dynamics, which in turn, may be associated with adverse health outcomes (here ASD is used as an example). The methodologies developed will be helpful to investigate molecular underpinnings of other micronutrients or toxicants on other health outcomes.
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0.904 |