Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington’s disease

Lee, Junghee,Hwang, Yu Jin,Shin, Jong-Yeon,Lee, Won-Chul,Wie, Jinhong,Kim, Ki Yoon,Lee, Min Young,Hwang, Daehee,Ratan, Rajiv R.,Pae, Ae Nim,Kowall, Neil W.,So, Insuk,Kim, Jong-Il,Ryu, Hoon Springer-Verlag 2013 Acta neuropathologica Vol.125 No.5

Epigenetic Mechanisms of Neurodegeneration in Huntington’s Disease

Lee, Junghee,Hwang, Yu Jin,Kim, Ki Yoon,Kowall, Neil W.,Ryu, Hoon Springer-Verlag 2013 Neurotherapeutics Vol.10 No.4

Three Temperature Model for Nonequilibrium Energy Transfer in Semiconductor Films Irradiated with Short Pulse Lasers

Lee, Seong Hyuk,Sim, Hyung Sub,Lee, Junghee,Kim, Jong Min,Shin, Young Eui The Japan Institute of Metals 2006 MATERIALS TRANSACTIONS Vol.47 No.11

<P>This article investigates numerically carrier-phonon interaction and nonequilibrium energy transfer in direct and indirect bandgap semiconductors during sub-picosecond pulse laser irradiation and also examines the recombination effects on energy transport from the microscopic viewpoint. In addition, the influence of laser fluence and pulse duration is studied by using the self-consistent three-temperature model, which involves carriers, longitudinal optical phonons, and acoustic phonons. It is found that a substantial non-equilibrium state exists between carriers and phonons during short pulse laser irradiation because of time scale difference between the relaxation time and the pulse duration. It is clear that the two-peak structure in carrier temperature exists and it depends mainly on laser pulses, fluences, and recombination processes. During laser irradiation, in particular, the Auger recombination for Si becomes dominant due to the increase in the carrier number density, whereas for GaAs, the Auger recombination process can be ignored due to an abrupt increase in SRH recombination rates at the initial stages of laser exposure.</P>

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Lee, Junghee,Kim, Yunha,Liu, Tian,Hwang, Yu Jin,Hyeon, Seung Jae,Im, Hyeonjoo,Lee, Kyungeun,Alvarez, Victor E.,McKee, Ann C.,Um, Soo‐,Jong,Hur, Manwook,Mook‐,Jung, Inhee,Kowall, Neil W.,Ry John Wiley and Sons Inc. 2018 Aging cell Vol.17 No.1

<P><B>Summary</B></P><P>Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.</P>

Activation of Ets‐2 by oxidative stress induces Bcl‐xL expression and accounts for glial survival in amyotrophic lateral sclerosis

Lee, Junghee,Kannagi, Mari,Ferrante, Robert J.,Kowall, Neil W.,Ryu, Hoon Federation of American Society for Experimental Bi 2009 The FASEB Journal Vol.23 No.6

<P>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective degeneration of motor neurons and glial activation. Cell-specific transcriptional regulation induced by oxidative stress may contribute to the survival and activation of astrocytes in the face of motor neuron death. In the present study, we demonstrate an age-dependent increase in Bcl-xL and Ets-2 immunoreactivity that correlates with an increase of glial fibrillary acidic protein (GFAP)-positive cells in the ventral horn of the spinal cord in both ALS transgenic mice [mutant SOD1 (G93A)] and affected humans. Chromatin immunoprecipitation (ChIP) analysis verified that Ets-2 preferentially occupies the Ets-2 binding element in the promoter of Bcl-xL in primary astrocytes under oxidative stress conditions as well as in G93A spinal cords. Ets-2 small-interfering RNA down-regulated the transcriptional activity of Bcl-xL. In primary glial cultures, Bcl-xL overexpression and mutant SOD1 (G93A) both conferred resistance to oxidative stress-induced cell death. Our findings suggest that Ets-2 transcription factor activation of Bcl-xL gene may protect glia from constitutive oxidative stress that is thought to be a key mechanism contributing to the pathogenesis of ALS. This survival pathway may contribute to the glial survival and activation seen in the spinal cord of ALS patients.</P>

Identification of differentially-expressed genes by DNA methylation in cervical cancer

LEE, HEUN-SIK,YUN, JUN HO,JUNG, JUNGHEE,YANG, YOUNG,KIM, BONG-JO,LEE, SUNG-JONG,YOON, JOO HEE,MOON, YONG,KIM, JEONG-MIN,KWON, YONG-IL D.A. Spandidos 2015 Oncology letters Vol.9 No.4

<P>To identify novel cervical cancer-related genes that are regulated by DNA methylation, integrated analyses of genome-wide DNA methylation and RNA expression profiles were performed using the normal and tumor regions of tissues from four patients; two with cervical cancer and two with pre-invasive cancer. The present study identified 19 novel cervical cancer-related genes showing differential RNA expression by DNA methylation. A number of the identified genes were novel cervical cancer-related genes and their differential expression was confirmed in a publicly available database. Among the candidate genes, the epigenetic regulation and expression of three genes, <I>CAMK2N1</I>, <I>ALDH1A3</I> and <I>PPP1R3C</I>, was validated in HeLa cells treated with a demethylating reagent using methylation-specific polymerase chain reaction (PCR) and quantitative PCR, respectively. From these results, the expression of the <I>CAMK2N1</I>, <I>ALDH1A3</I> and <I>PPP1R3C</I> genes are were shown to be suppressed in cervical cancers by DNA methylation. These genes may be involved in the progression or initiation of cervical cancer.</P>

EWSR1, a multifunctional protein, regulates cellular function and aging via genetic and epigenetic pathways

Lee, Junghee,Nguyen, Phuong T.,Shim, Hyun Soo,Hyeon, Seung Jae,Im, Hyeonjoo,Choi, Mi-Hyun,Chung, Sooyoung,Kowall, Neil W.,Lee, Sean Bong,Ryu, Hoon Elsevier 2019 Biochimica et biophysica acta. Molecular basis of Vol.1865 No.7

<P><B>Abstract</B></P> <P>Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. <I>EWSR1</I> (<I>Ewing Sarcoma breakpoint region 1</I>/<I>EWS RNA binding protein 1</I>) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of <I>EWSR1</I> genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. <I>Ewsr1</I> deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what <I>EWSR1</I> genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders.</P> <P><B>Highlights</B></P> <P> <UL> <LI> EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) has diverse roles in various cellular processes. </LI> <LI> Missense mutations of <I>EWSR1</I> are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). </LI> <LI> EWSR1 deficiency also contributes to hematopoietic stem cell senescence. </LI> <LI> EWSR1 participates in mitochondria function and cellular energy homeostasis by modulating the stability of PGC-1α. </LI> <LI> EWSR1 deficiency deregulates dopaminergic signaling pathways by reducing TH activity and leads to motor dysfunction. </LI> </UL> </P>

Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington’s disease

Lee, Junghee,Hwang, Yu Jin,Kim, Yunha,Lee, Min Young,Hyeon, Seung Jae,Lee, Soojin,Kim, Dong Hyun,Jang, Sung Jae,Im, Hyoenjoo,Min, Sun-Joon,Choo, Hyunah,Pae, Ae Nim,Kim, Dong Jin,Cho, Kyung Sang,Kowall Springer Verlag 2017 Acta neuropathologica Vol.134 No.5

<P>Huntington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. Altered histone modifications and epigenetic mechanisms are closely associated with HD suggesting that transcriptional repression may play a pathogenic role. Epigenetic compounds have significant therapeutic effects in cellular and animal models of HD, but they have not been successful in clinical trials. Herein, we report that dSETDB1/ESET, a histone methyltransferase (HMT), is a mediator of mutant HTT-induced degeneration in a fly HD model. We found that nogalamycin, an anthracycline antibiotic and a chromatin remodeling drug, reduces trimethylated histone H3K9 (H3K9me3) levels and pericentromeric heterochromatin condensation by reducing the expression of Setdb1/Eset. H3K9me3-specific ChIP-on-ChIP analysis identified that the H3K9me3-enriched epigenome signatures of multiple neuronal pathways including Egr1, Fos, Ezh1, and Arc are deregulated in HD transgenic (R6/2) mice. Nogalamycin modulated the expression of the H3K9me3-landscaped epigenome in medium spiny neurons and reduced mutant HTT nuclear inclusion formation. Moreover, nogalamycin slowed neuropathological progression, preserved motor function, and extended the life span of R6/2 mice. Together, our results indicate that modulation of SETDB1/ESET and H3K9me3-dependent heterochromatin plasticity is responsible for the neuroprotective effects of nogalamycin in HD and that small compounds targeting dysfunctional histone modification and epigenetic modification by SETDB1/ESET may be a rational therapeutic strategy in HD.</P>

<small>FeSSD</small>: A Fast Encrypted SSD Employing On-Chip Access-Control Memory

Lee, Junghee,Ganesh, Kalidas,Lee, Hyuk-Jun,Kim, Youngjae IEEE 2017 IEEE computer architecture letters Vol.16 No.2

<P>Cryptography is one of the most popular methods for protecting data stored in storage devices such as solid-state drives (SSDs). To maintain integrity of data, one of the popular techniques is that all incoming data are encrypted before they are stored, however, in this technique, the encryption overhead is non-negligible and it can increase I/O service time. In order to mitigate the negative performance impact caused by the data encryption, a write buffer can be used to hide the long latency by encryption. Using the write buffer, incoming unencrypted data can be immediately returned as soon as they are written in the buffer. They will get encrypted and synchronized with flash memory. However, if the write buffer itself is not encrypted, unencrypted secret data might leak through this insecure write buffer. On the other hand, if the entire write buffer is fully encrypted, it incurs significant performance overhead. To address this problem, we propose an on-chip access control memory (ACM) and presents a fast encrypted SSD, called <SMALL>FeSSD</SMALL> that implements a secure write buffering mechanism using the ACM. The ACM does not require a memory-level full encryption mechanism, thus not only solving the unencrypted data leaking problem, but also offering relatively fast I/O service. Our simulation results show that the I/O response time of <SMALL>FeSSD</SMALL> can be improved by up to 56 percent over a baseline where encrypted data are stored in the normal write buffer.</P>

MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS

Lee, Jae Keun,Shin, Jin Hee,Hwang, Sang Gil,Gwag, Byoung Joo,McKee, Ann C.,Lee, Junghee,Kowall, Neil W.,Ryu, Hoon,Lim, Dae-Sik,Choi, Eui-Ju National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.29

<P>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species–dependent manner. Moreover, MST1 was found to mediate SOD1(G93A)-induced activation of p38 mitogen-activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS.</P>