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>

Evolution of Coffee Flavor in Short-term Storage by Colorimetric Sensor Array

Junghee Woo,Hyun Jin Park 한국식품영양과학회 2019 한국식품영양과학회 학술대회발표집 Vol.2019 No.10

Mitochondrial Targeting Domain Homologs Induce Necrotic Cell Death Via Mitochondrial and Endoplasmic Reticulum Disruption

( Junghee Park ),( Ji-hye Han ),( Seung-hyun Myung ),( Hea-jong Chung ),( Jae-il Park ),( Ju-yeon Cho ),( Tae-hyoung Kim ) 한국미생물생명공학회(구 한국산업미생물학회) 2021 Journal of microbiology and biotechnology Vol.31 No.6

The mitochondrial targeting domain (MTD) of Noxa contributes to its mitochondrial localization and to apoptosis induction. As a peptide, MTD fused with octa-arginine (R8), a CPP, induces necrosis related to intracellular calcium influx and destruction of mitochondria and endoplasmic reticulum. We searched for homologs of MTD, and compared their cell killing capability when fused with R8. Three of the seven peptides triggered cell death with similar mechanisms. The comparative analysis of peptide sequences showed that four amino acid sites of MTD are critical in regulating necrosis, suggesting the potential to generate artificial, adjustable cytotoxic peptides, which could be effective medicines for many diseases. Thus, homologs functionality could hint to the functions of their belonging proteins.

IKK‐β‐mediated myeloid cell activation exacerbates inflammation and inhibits recovery after spinal cord injury

Kang, Junghee,Jiang, Mei Hua,Min, Hyun Jung,Jo, Eun‐,Kyeong,Lee, Soojin,Karin, Michael,Yune, Tae Young,Lee, Sung Joong WILEY‐VCH Verlag 2011 European journal of immunology Vol.41 No.5

<P><B>Abstract</B></P><P>Traumatic spinal cord injury (SCI) is followed by massive infiltration and activation of myeloid cells such as neutrophils and macrophages, but the functions of these cells are controversial. In this study, our objective was to elucidate the in vivo role of a signaling pathway involved in activation of these innate immune cells in SCI using myeloid cell‐specific IκB kinase (IKK)‐β conditional knockout (<TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-1.gif' alt ='equation image'/> ) mice. In these mice, the <I>ikk</I>β gene has been specifically deleted from myeloid cells, compromising their in vivo IKK/NF‐κB‐dependent activation. We found that <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-2.gif' alt ='equation image'/> mice had significantly reduced neutrophil and macrophage infiltrations after SCI compared to <I>ikk</I>β<SUP>+/+</SUP> controls. SCI‐induced proinflammatory gene expression was also reduced in <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-3.gif' alt ='equation image'/> mice. Reduced neuroinflammation in <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-4.gif' alt ='equation image'/> mice was accompanied by attenuated neuronal loss and behavioral deficits in motor activity. In addition, the SCI‐induced expression of CXC ligand 1 was reduced in <TEX>${\rm {ikk}}{\rm {\beta}}^{\Delta mye}$</TEX><IMG src='/wiley-blackwell_img/equation/tex2gif-ueqn-5.gif' alt ='equation image'/> mice, which may be responsible for the reduced neutrophil infiltration in these mice. Our data demonstrate that IKK‐β‐dependent myeloid cell activation potentiates neuroinflammation and neuronal damage after SCI.</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>

A peptide containing Noxa mitochondrial-targeting domain induces cell death via mitochondrial and endoplasmic reticulum disruption

Park, Junghee,Han, Ji-Hye,Myung, Seung-Hyun,Kang, Hyuno,Cho, Ju-Yeon,Kim, Tae-Hyoung Academic Press 2019 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>Noxa is a weak apoptosis activator consisting of a BH3 domain and a mitochondrial-targeting domain (MTD). BH3 binds Mcl-1 and Bcl2A1 and inactivates their anti-apoptotic activities, while MTD delivers BH3 to mitochondria. Previously we revealed that MTD may also function as an inducer of necrosis via conjugation with octa-arginine, which induces cytosolic Ca<SUP>2+</SUP> influx from mitochondria. However, the mechanism(s) underlying this process has not been elucidated yet. Here, we show that calcium influx induced by an MTD peptide fused with octa-arginine residue (R8:MTD) originates not only from mitochondria but also from the extracellular space. However, calcium spikes were not sufficient for necrosis. R8:MTD induced mitochondrial permeability transition pore opening, fragmentation, and swelling. These mitochondrial events induced by MTD appeared to be necessary for necrosis induction, since DIDS, a VDAC inhibitor, inhibited the mitochondrial swelling and cell death induced by MTD. We show that R8:MTD disrupted endoplasmic reticulum (ER) structures but not peroxisomes or Golgi, indicating that R8:MTD causes necrosis by inducing ER events as well.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MTD peptide fused with 8-arginine (R8:MTD) induced necrotic cell death. </LI> <LI> R8:MTD induced Ca<SUP>2+</SUP> influx from mitochondria and extracellular space. </LI> <LI> MTD interacted with VDAC, and induced mitochondrial catastrophe. </LI> <LI> VDAC inhibitor DIDS inhibited cell death and mitochondrial disruption. </LI> <LI> R8:MTD disrupted ER where VDAC was expressed. </LI> </UL> </P>

MTD-like motif of a BH3-only protein, BNIP1, induces necrosis accompanied by an intracellular calcium spike

Park, Junghee,Han, Ji-Hye,Myung, Seung-Hyun,Seo, Young-Woo,Kim, Tae-Hyoung Elsevier 2018 Biochemical and biophysical research communication Vol.495 No.2

<P><B>Abstract</B></P> <P>The mitochondrial targeting domain (MTD) of Noxa has necrosis-inducing activity when conjugated with cell-penetrating peptide (CPP). In this study, we report another MTD-like motif, B1MLM, found in BNIP1, a pro-apoptotic BH3-only protein found in the endoplasmic reticulum membrane. The B1MLM peptide, conjugated with CPP, induced necrosis in a way similar to that of R8:MTD. R8:B1MLM caused an intracellular calcium spike, mitochondrial reactive oxygen species generation, and mitochondrial fragmentation. The cytosolic calcium spike was likely due to the opening of the mitochondrial permeability transition pore.</P>

Controlled Charge Trapping and Retention in Large-Area Monodisperse Protein Metal-Nanoparticle Conjugates

Kim, Chang-Hyun,Bhak, Ghibom,Lee, Junghee,Sung, Sujin,Park, Sungjun,Paik, Seung R.,Yoon, Myung-Han American Chemical Society 2016 ACS APPLIED MATERIALS & INTERFACES Vol.8 No.19

<P>Here, we report on charge-retention transistors based on novel protein-mediated Au nanoparticle (NP) arrays, with precise control over dimension and distribution. Individual NPs are coated with alpha-synuclein, an amyloidogenic protein responsible for Lewy body formation in Parkinson's disease. Subsequently, a monolayer of protein-NP conjugates is successfully created via a simple and scalable solution deposition to function as distributed nanoscale capacitors. Controllability over the film structure translates into the tunability of the electrical performance; pentacene-based organic transistors feature widely varying programmability and relaxation dynamics, providing versatility for various unconventional memory applications.</P>

유턴을 고려한 교통축 적용 수요대응 자율주행 대중교통(DRDTO)의 실시간 동적 경로 생성 알고리즘

김현(KIM, Hyun),유선형(YOO, Seonhyung),이진우(LEE, Jinwoo),백범열(BAEK, Beomyeol),신정희(SHIN, Junghee) 대한교통학회 2022 대한교통학회지 Vol.40 No.2

최근 자율주행 차량이 대중교통분야로 진출하여 관련 연구들이 활발히 진행되고 있다. 본 연구에서는 시공간적으로 다양하게 발생하는 실시간 호출수요에 대응하여 자율주행 차량에 동적 경로를 제시하여 효율적인 대중교통 서비스를 제공할 수 있는 알고리즘을 개발했다. 실시간 호출수요는 다수의 출발지와 다수의 목적지로 구성되어 복잡하고 다양한 경우의 수를 고려하여 최적 경로를 제시할 수 있는 방안이 필수적이다. 복잡한 계산과정은 오프라인 과정에서 선행할 수 있는 방법으로 머신러닝의 강화학습 기술을 사용하여 제시하였다. 개발된 자율주행 대중교통(DTO)를 위한 실시간 호출 수요대응 동적경로 알고리즘은 테스트베드를 선정하여 시뮬레이션 실험이 이루어 졌다. 시뮬레이션 결과는 개발된 실시간 호출 수요대응 동적경로 생성 알고리즘을 고정노선의 운행결과 대비하여 효율적인 운행결과가 나타났다. 이는 실시간 호출수요량이 적을수록 효과가 크게 나타나지만 호출 수요량이 증가하면서 그 효과 폭이 점차적으로 감소했다. Recently, autonomous vehicle is receiving much attention in various sectors including transportation and public transportation. This study presents an adaptive routing algorithm for the real-time demand response service of autonomous transit vehicles. The experimental setting includes the real-time demand occurring randomly over time within the study area. Each demand (service call) request the transit service from designated origin to destination. The routing algorithm is designed to make U-turn and skip stops to improve service and reduce the wait time of users. This study adapts Reinforcement Learning, one of the machine learning techniques, namely reinforcement learning, which can precede a complex calculation process in an offline process. Simulation experiments conducted on a testbed of the Chungju campus of the Korea National University of Transportation. The simulation results show that the proposed routing algorithm can improve the adaptive transit service over the fixed operation in selected performance indicators.

Acupuncture for Spasticity after Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Lim, Sung Min,Yoo, Junghee,Lee, Euiju,Kim, Hyun Jung,Shin, Seungwon,Han, Gajin,Ahn, Hyeong Sik Hindawi Publishing Corporation 2015 Evidence-based Complementary and Alternative Medic Vol.2015 No.-

<P>The aim of this systematic review was to determine how effective acupuncture or electroacupuncture (acupuncture with electrical stimulation) is in treating poststroke patients with spasticity. We searched publications in Medline, EMBASE, and the Cochrane Library in English, 19 accredited journals in Korean, and the China Integrated Knowledge Resources Database in Chinese through to July 30, 2013. We included randomized controlled trials (RCTs) with no language restrictions that compared the effects of acupuncture or electroacupuncture with usual care or placebo acupuncture. The two investigators assessed the risk of bias and statistical analyses were performed. Three RCTs in English, 1 in Korean, and 1 in Chinese were included. Assessments were performed primarily with the Modified Ashworth Scale (MAS). Meta-analysis showed that acupuncture or electroacupuncture significantly decreased spasticity after stroke. A subgroup analysis showed that acupuncture significantly decreased wrist, knee, and elbow spasticity in poststroke patients. Heterogeneity could be explained by the differences in control, acupoints, and the duration after stroke occurrence. In conclusion, acupuncture could be effective in decreasing spasticity after stroke, but long-term studies are needed to determine the longevity of treatment effects.</P>