Huntington's disease (HD) is an incurable progressive autosomal-dominant neurological disorder caused by expanded CAG repeats coding for glutamine in the huntingtin (Htt) gene but it is not known how this mutation causes neurodegeneration. We recently discovered that alterations of ERG- associated protein with SET domain (ESET) expression and hypermethylation of histone H3K9 correlate with transcriptional dysfunction and neurodegeneration in two different transgenic mouse models of HD. Furthermore, in experiments using CREB binding protein (CBP) knockout mice, we found that CBP deficiency leads to histone hypermethylation and transcriptional deregulation by freeing Ets-2 to bind and activate the ESET gene thereby linking CBP deficiency to histone hypermethylation and neuronal degeneration. Our preliminary data shows that that brain CBP levels are reduced in HD transgenic mice and we confirmed, as reported by others, that mutant htt sequesters CBP. We hypothesize that mtHtt sequesters CBP resulting in greater availability of free Ets-2 to bind the ESET gene promoter region and increase ESET transcription. Increased ESET transcription in turn leads to hypermethylation of histone H3K9, transcriptional dysfunction, heterochromatin condensation and neurodegeneration in HD. We theorize that the trimethylated histone H3K9 (TMH3K9) mediates the epigenetic and transcriptional dysregulation that underlies disease progression of transgenic HD mice. We propose to test our hypothesis through three specific aims:
Specific Aim 1 : To determine under what mechanisms mtHtt and CBP modulates expression of the ESET gene, a histone H3K9 specific methyltransferase, and leads to chromatin remodeling.
Specific Aim2 : To examine how ESET modulates hyper-trimethylation of H3K9 (TMH3K9) and results in heterochromatin condensation and gene silencing. We will analyze the TMH3K9-dependent heterochromatin condensation by confocal microscopy combining deconvolution and 3-dimentional reconstruction of images. We will identify what genomes are silenced or modulated by TMH3K9 using ChIP and full genome sequencing analysis.
Specific Aim 3 : To cross mice genetically deficient in CBP (heterozygote and knockout) and ESET transgenic mice with the HD mice to determine the relationship among alterations of HMT gene expression, TMH3K9, and neuropathological phenotype and survival of crossed mice. Our proposed study will provide new insights and molecular mechanisms on the role of chromatin remodeling and gene silencing in the pathogenesis of HD. Considering a fact that epigenetic regulation is a strong candidate method from a therapeutic perspective, our mechanistic study will contirbute to finding of the novel therapeutic target and epigenetic biomarker in HD.
Huntington's disease (HD) is a fatal progressive hereditary neurological disease caused by mutations of the huntingtin (Htt) gene but it is not known how this mutation leads to nerve cell death. Changes in proteins called histones, which bind to DNA and regulate gene expression, are suspected to be involved but little is known about how this occurs. In this regard, our study focuses on enzymes and genes involved in controlling how histones interact with DNA and control gene expression. This research could lead to the development of novel biological markers for HD onset and progression and will provide new information about how DNA and its associated proteins are organized in the nucleus of neurons. This finding will allow us to develop a new therapeutic approach that contributes to preclinical and human trials in the future.
|Kim, Dohee; Jeon, Jeha; Cheong, Eunji et al. (2016) Neuroanatomical Visualization of the Impaired Striatal Connectivity in Huntington's Disease Mouse Model. Mol Neurobiol 53:2276-86|
|Lee, Chai-Jin; Ahn, Hongryul; Lee, Sean Bong et al. (2016) Integrated analysis of omics data using microRNA-target mRNA network and PPI network reveals regulation of Gnai1 function in the spinal cord of Ews/Ewsr1 KO mice. BMC Med Genomics 9 Suppl 1:33|
|Jung, Eun Sun; Choi, Hyunjung; Song, Hyundong et al. (2016) p53-dependent SIRT6 expression protects AÎ²42-induced DNA damage. Sci Rep 6:25628|
|Kim, Yunha; Lee, Junghee; Ryu, Hoon (2015) Modulation of autophagy by miRNAs. BMB Rep 48:371-2|
|Hong, Chansik; Seo, Hyemyung; Kwak, Misun et al. (2015) Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington's disease. Brain 138:3030-47|
|Kim, Yunha; Kang, Young-Sook; Lee, Na-Young et al. (2015) Uvrag targeting by Mir125a and Mir351 modulates autophagy associated with Ewsr1 deficiency. Autophagy 11:796-811|
|Lee, J; Ryu, H; Keum, G et al. (2014) Therapeutic targeting of epigenetic components in amyotrophic lateral sclerosis (ALS). Curr Med Chem 21:3576-82|
|Koh, Dong-In; Han, Dohyun; Ryu, Hoon et al. (2014) KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes. Proc Natl Acad Sci U S A 111:15078-83|
|Kim, K Y; Hwang, Y J; Jung, M-K et al. (2014) A multifunctional protein EWS regulates the expression of Drosha and microRNAs. Cell Death Differ 21:136-45|
|Hwang, Yu Jin; Han, Dohyun; Kim, Ki Yoon et al. (2014) ESET methylates UBF at K232/254 and regulates nucleolar heterochromatin plasticity and rDNA transcription. Nucleic Acids Res 42:1628-43|
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