Epigenetic regulation of microRNAs in neurogenesis Histone deacetylase (HDAC) inhibitors such as valproate (VPA) are commonly used to treat epilepsy. One me- chanism of their efficacy may result from epigenetic effects on differentiation of neural precursors. While HDAC inhibitors are likely to affect mRNA-encoding genes, we believe that the rapid regulation of microRNAs by VPA treatment suggests a novel complementary mechanism. Hypothesis: Acetylated histones allow expression of microRNAs that enhance or support neurogenesis from neural precursors. Therefore, adding an HDAC inhibitor allows the accumulation of acetyl marks on microRNA-encoding sites on the chromatin, in turn enhancing expression of the marked microRNAs, which contribute to neural differentiation. We will test the hypothesis by using """"""""deep sequencing"""""""" to identify the full complement of VPA-regulated microRNAs, including hundreds of novel microRNAs that we recently identified in neural differentiation. Finally, we will build on our preliminary studies with microRNA inhibitors and screening techniques to evaluate candidate microRNAs for their requirement for VPA-induced neuronal differentiation. Results from these three aims will identify both known and putatively novel microRNAs that are regulated after HDAC inhibition, the acetylation status of histones located near microRNA promoter regions, and whether the regulated microRNAs contribute to neuronal differentiation. Understanding the regulatory networks required for neurogenesis is important for determining how differentiation of neural precursors could be impaired in conditions such as dementia, Parkinson's, or stroke. Alternatively, the use of HDAC inhibitors in conditions such as epilepsy, bipolar disorder, or migraines may have unexpected effects on neurogenesis from adult precursors, and this potential benefit should be understood.
Epigenetic regulation of microRNAs in neurogenesis. Epilepsy drugs such as valproate (VPA) are known to inhibit histone deacetylases, which control gene expression epigenetically. Since VPA also increases the production of neurons from adult stem cells or other precursors, we believe that VPA may regulate microRNA genes, in turn affecting decisions controlling cell differentiation. We will use """"""""deep sequencing"""""""" of microRNAs and gene regulatory regions to identify novel neurogenesis mechanisms.
|DeBoer, E M; Kraushar, M L; Hart, R P et al. (2013) Post-transcriptional regulatory elements and spatiotemporal specification of neocortical stem cells and projection neurons. Neuroscience 248:499-528|
|Li, Jiali; Hart, Ronald P; Mallimo, Elyse M et al. (2013) EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia. Nat Neurosci 16:1745-53|
|Komlos, Daniel; Mann, Kara D; Zhuo, Yue et al. (2013) Glutamate dehydrogenase 1 and SIRT4 regulate glial development. Glia 61:394-408|
|Ricupero, Christopher L; Swerdel, Mavis R; Hart, Ronald P (2013) Epigenome analysis of pluripotent stem cells. Methods Mol Biol 997:203-16|
|Pichardo-Casas, Israel; Goff, Loyal A; Swerdel, Mavis R et al. (2012) Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation. Brain Res 1436:20-33|
|Li, Hedong; Hader, Anna T; Han, Yu R et al. (2012) Isolation of a novel rat neural progenitor clone that expresses Dlx family transcription factors and gives rise to functional GABAergic neurons in culture. Dev Neurobiol 72:805-20|
|Mahishi, Lata H; Hart, Ronald P; Lynch, David R et al. (2012) miR-886-3p levels are elevated in Friedreich ataxia. J Neurosci 32:9369-73|
|Li, Jiali; Chen, Jianmin; Ricupero, Christopher L et al. (2012) Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. Nat Med 18:783-90|
|Ma, Liping; Yu, Young-Mi; Guo, Yuji et al. (2012) Cysteine- and glycine-rich protein 1a is involved in spinal cord regeneration in adult zebrafish. Eur J Neurosci 35:353-65|
|Camarillo, Cynthia; Swerdel, Mavis; Hart, Ronald P (2011) Comparison of microarray and quantitative real-time PCR methods for measuring MicroRNA levels in MSC cultures. Methods Mol Biol 698:419-29|
Showing the most recent 10 out of 16 publications