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Seoul, South Korea

Shin J.,Seoul National University | Shin J.,Psoma Therapeutics Inc. | Yu S.-B.,Seoul National University | Yu S.-B.,Psoma Therapeutics Inc. | And 3 more authors.
BMB Reports | Year: 2010

The Swedish mutation (K595N/M596L) of amyloid precursor protein (APP-swe) has been known to increase abnormal cleavage of cellular APP by Beta-secretase (BACE), which causes tau protein hyperphosphorylation and early-onset Alzheimer's disease (AD). Here, we analyzed the effect of APP-swe in global gene expression using deep transcriptome sequencing technique. We found 283 genes were down-regulated and 348 genes were up-regulated in APP-swe expressing H4-swe cells compared to H4 wild-type cells from a total of approximately 74 million reads of 38 base pairs from each transcriptome. Two independent mechanisms such as kinase and phosphatase signaling cascades leading hyperphosphorylation of tau protein were regulated by the expression of APP-swe. Expressions of catalytic subunit as well as several regulatory subunits of protein phosphatases 2A were decreased. In contrast, expressions of tau-phosphorylating glycogen synthase kinase 3β (GSK-3β), cyclin dependent kinase 5 (CDK5), and cAMP-dependent protein kinase A (PKA) catalytic subunit were increased. Moreover, the expression of AD-related Aquaporin 1 and presenilin 2 expression was regulated by APP-swe. Taken together, we propose that the expression of APP-swe modulates global gene expression directed to AD pathogenesis.


Kim K.H.,Seoul National University | Moon M.,Seoul National University | Yu S.-B.,Psoma Therapeutics Inc. | Mook-Jung I.,Seoul National University | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2012

The pathogenesis of Alzheimer's disease (AD), especially the early events of AD pathology, remains unknown because of the complexity of AD and limitation of analysis methods. Transcriptome analysis has provided comprehensive insights to investigate the complex cellular activity in brain, but the transcriptome profiles from AD patients with microarray have generated discordant results. Here, for the first time, we performed transcriptome analysis of frontal cortex and cerebellum in 7-week-old 5XFAD transgenic mice (before extracellular amyloid plaque deposits) using high-throughput RNA-Seq analysis. Specific functional annotations were identified with differentially expressed genes (DEGs) of frontal cortex (a typically vulnerable region of AD pathology) and cerebellum (a typically non-vulnerable region of AD pathology). Cardiovascular disease-related genes were significantly found in down-regulated DEGs of frontal cortex, and mitochondrial dysfunction-related genes were evident in down-regulated DEGs of cerebellum. Additionally, we found RNA variants at the nucleotide level in transgenic mice compared with non-transgenic mice. Our results indicate that both frontal cortex and cerebellum in 5XFAD transgenic mice show specific pathological processes in the early pathophysiology of AD. © 2012-IOS Press and the authors. All rights reserved.


Lee J.,Veterans Affairs Boston Healthcare System | Lee J.,Boston University | Hwang Y.J.,Seoul National University | Shin J.-Y.,Seoul National University | And 16 more authors.
Acta Neuropathologica | Year: 2013

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded trinucleotide CAG repeat in the gene coding for huntingtin. Deregulation of chromatin remodeling is linked to the pathogenesis of HD but the mechanism remains elusive. To identify what genes are deregulated by trimethylated histone H3K9 (H3K9me3)-dependent heterochromatin, we performed H3K9me3-ChIP genome-wide sequencing combined with RNA sequencing followed by platform integration analysis in stable striatal HD cell lines (STHdhQ7/7 and STHdhQ111/111) cells. We found that genes involving neuronal synaptic transmission including cholinergic receptor M1 (CHRM1), cell motility, and neuronal differentiation pathways are downregulated while their promoter regions are highly occupied with H3K9me3 in HD. Moreover, we found that repression of CHRM1 gene expression by H3K9me3 impairs Ca2+-dependent neuronal signal transduction in stable cell lines expressing mutant HD protein. Thus, our data indicate that the epigenetic modifications, such as aberrant H3K9me3-dependent heterochromatin plasticity, directly contribute to the pathogenesis of HD. © Springer-Verlag Berlin Heidelberg 2013.


Hwang Y.,Brain Bio | Kim J.,Brain Bio | Shin J.-Y.,Seoul National University | Shin J.-Y.,Psoma Therapeutics Inc. | And 8 more authors.
Translational Psychiatry | Year: 2013

Whole-genome expression profiling in postmortem brain tissue has recently provided insight into the pathophysiology of schizophrenia. Previous microarray and RNA-Seq studies identified several biological processes including synaptic function, mitochondrial function and immune/inflammation response as altered in the cortex of subjects with schizophrenia. Now using RNA-Seq data from the hippocampus, we have identified 144 differentially expressed genes in schizophrenia cases as compared with unaffected controls. Immune/inflammation response was the main biological process over-represented in these genes. The upregulation of several of these genes, IFITM1, IFITM2, IFITM3, APOL1 (Apolipoprotein L1), ADORA2A (adenosine receptor 2A), IGFBP4 and CD163 were validated in the schizophrenia subjects using data from the SNCID database and with quantitative RT-PCR. We identified a co-expression module associated with schizophrenia that includes the majority of differentially expressed genes related to immune/inflammation response as well as with the density of parvalbumin-containing neurons in the hippocampus. The results indicate that abnormal immune/inflammation response in the hippocampus may underlie the pathophysiology of schizophrenia and may be associated with abnormalities in the parvalbumin-containing neurons that lead to the cognitive deficits of the disease. © 2013 Macmillan Publishers Limited All rights reserved.


Ju Y.S.,Seoul National University | Ju Y.S.,Macrogen Inc. | Lee W.-C.,Seoul National University | Shin J.-Y.,Seoul National University | And 11 more authors.
Genome Research | Year: 2012

The identification of the molecular events that drive cancer transformation is essential to the development of targeted agents that improve the clinical outcome of lung cancer. Many studies have reported genomic driver mutations in non-small-cell lung cancers (NSCLCs) over the past decade; however, the molecular pathogenesis of >40%of NSCLCs is still unknown. To identify new molecular targets in NSCLCs, we performed the combined analysis of massively parallel whole-genome and transcriptome sequencing for cancer and paired normal tissue of a 33-yr-old lung adenocarcinoma patient, who is a never-smoker and has no familial cancer history. The cancer showed no known driver mutation in EGFR or KRAS and no EML4-ALK fusion. Here we report a novel fusion gene between KIF5B and the RET proto-oncogene caused by a pericentric inversion of 10p11.22-q11.21. This fusion gene overexpresses chimeric RET receptor tyrosine kinase, which could spontaneously induce cellular transformation. We identified the KIF5B-RET fusion in two more cases out of 20 primary lung adenocarcinomas in the replication study.Our data demonstrate that a subset ofNSCLCs could be caused by a fusion of KIF5B and RET, andsuggest the chimeric oncogene as a promising molecular target for the personalized diagnosis and treatment of lung cancer. © 2012 by Cold Spring Harbor Laboratory Press.

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