Molecular Mechanism of Apicidin-Induced Down-regulation of DNA Methyltransferase 1 Expression

HAN Jeung Whan,YOU Jueng Soo,LEE Eunkyung,KANG Gil Myoung,KO Dae Hwan,JEON Ye Ji,KIM Nam Wook,CHOI Wahn Soo 대한약학회 2006 大韓藥學會 總會 및 學術大會 Vol.2006 No.2

Targeting components of epigenome by small molecules.

You, Jueng Soo,Han, Jeong Hwan Pharmaceutical Society of Korea 2014 Archives of Pharmacal Research Vol.37 No.11

<P>The diverse epigenetic modifications regulate the gene expression and determine the cellular identity. Pioneering work over the past decades has highlighted that these epigenetic regulations establish normal development but also contribute various diseases. Furthermore, the epigenetic priming events are considered as a key factor for efficient master transcription factor(s) mediated reprogramming process. With the advent of numerous small molecules that target specific enzymes or proteins involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as a valuable approach to cancer therapy and cellular reprogramming. Here, we briefly present the basic principles of epigenetic regulations and review the recent application of epigenetic targeting small molecules.</P>

천식 소아에서 혈중 포스포리파제 A2: leptin과 운동유발 기관지과민성과의 상관성

유정섭 ( Jueng Sup You ),최원복 ( Won Bok Choi ),이윤영 ( Yoon Young Yi ),정수인 ( Soo In Jeong ),송준섭 ( Joon Sup Song ),양승 ( Seong Yang ),황일태 ( Il Tae Hwang ),이하백 ( Ha Baik Lee ),백혜성 ( Hey Sung Baek ) 대한천식알레르기학회 2015 Allergy Asthma & Respiratory Disease Vol.3 No.2

Purpose: Dysregulated cysteinyl leukotriene (CysLT) synthesis is prominent in exercise-induced bronchoconstriction (EIB). Secreted phospholipase A2 (sPLA2) plays a key regulatory role in the biosynthesis of CysLTs. We previously found that serum leptin levels cor￢relate with (EIB) in children with asthma. The aim of this study was to address the relationship between plasma sPLA2/leptin levels and EIB. Methods: Sixty-seven prepubertal children between the ages of 6 and 10 years were included in the study. They were asthmatics with EIB (n=25), asthmatics without EIB (n=21), and healthy subjects (n=21). We measured the plasma sPLA2 and leptin levels. We also performed pulmonary function tests at baseline, after bronchodilator inhalation, and after exercise. Results: The sPLA2 and leptin levels were significantly higher in asthmatics with EIB than in those without and control subjects. In addition, sPLA2 levels were significantly correlated with body mass index (Speraman correlation coefficient r=0.343, P=0.023) and leptin levels (partial correlation coefficient r=318, P=0.033). The maximum decrease in % forced expiratory volume in 1 second af￢ter exercise was significantly correlated with both PLA2 levels (r=0.301, P=0.041) and leptin levels (r=0.346, P=0.018). Conclusion: The sPLA2 and leptin levels were significantly higher in asthmatics with EIB than in asthmatics without EIB and control subjects. In addition, sPLA2 levels were significantly correlated with leptin levels and EIB in asthmatic children.(Allergy Asthma Respir Dis 2015;3:99-104)

Urinary Proteome Profile Predictive of Disease Activity in Rheumatoid Arthritis

Kang, Min Jueng,Park, Yune-Jung,You, Sungyong,Yoo, Seung-Ah,Choi, Susanna,Kim, Dong-Ho,Cho, Chul-Soo,Yi, Eugene C.,Hwang, Daehee,Kim, Wan-Uk American Chemical Society 2014 JOURNAL OF PROTEOME RESEARCH Vol.13 No.11

<P>Current serum biomarkers for rheumatoid arthritis (RA) are not highly sensitive or specific to changes of disease activities. Thus, other complementary biomarkers have been needed to improve assessment of RA activities. In many diseases, urine has been studied as a window to provide complementary information to serum measures. Here, we conducted quantitative urinary proteome profiling using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and identified 134 differentially expressed proteins (DEPs) between RA and osteoarthritis (OA) urine samples. By integrating the DEPs with gene expression profiles in joints and mononuclear cells, we initially selected 12 biomarker candidates related to joint pathology and then tested their altered expression in independent RA and OA samples using enzyme-linked immunosorbent assay. Of the initial candidates, we selected four DEPs as final candidates that were abundant in RA patients and consistent with those observed in LC–MS/MS analysis. Among them, we further focused on urinary soluble CD14 (sCD14) and examined its diagnostic value and association with disease activity. Urinary sCD14 had a diagnostic value comparable to conventional serum measures and an even higher predictive power for disease activity when combined with serum C-reactive protein. Thus, our urinary proteome provides a diagnostic window complementary to current serum parameters for the disease activity of RA.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jprobs/2014/jprobs.2014.13.issue-11/pr500467d/production/images/medium/pr-2014-00467d_0006.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/pr500467d'>ACS Electronic Supporting Info</A></P>

SOX9 is controlled by the BRD4 inhibitor JQ1 via multiple regulation mechanisms

Hong, Seong Hwi,You, Jueng Soo Elsevier 2019 Biochemical and biophysical research communication Vol.511 No.4

<P><B>Abstract</B></P> <P>SOX9 is a key transcription factor during cell differentiation, sex determination, and tumorigenesis. However, the detailed mechanisms of its targeting strategy remain elusive. To investigate possibilities of targeting SOX9 with epigenetic drugs and the precise underlying mechanisms, two human cancer cell lines were chosen as model systems, which showed high SOX9 expression and anti-tumorigenic effects upon loss of SOX9. Histone acetylation-related screening of a small panel of epigenetic drugs revealed that the bromodomain reader inhibitor JQ1 dramatically downregulated SOX9 through multiple regulation steps, namely, transcription, BRD4-SOX9 protein–protein interaction, and further protein stability. These findings suggest that BRD4 inhibition is a novel therapeutic strategy for diseases characterized by SOX9 overexpression.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Oncogenic SOX9 is downregulated by the BET inhibitor JQ1. </LI> <LI> JQ1 represses transcription via reduced BRD4 binding to SOX9 DNA regulatory regions. </LI> <LI> JQ1 interferes with the protein interactions between SOX9 and BRD4. </LI> <LI> The protein stability of SOX9 is decreased by JQ1. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Senescence and impaired DNA damage responses in alpha-synucleinopathy models

Yoon Ye-Seul,You Jueng Soo,Kim Tae-Kyung,Ahn Woo Jung,Kim Myoung Jun,Son Keun Hong,Ricarte Diadem,Ortiz Darlene,Lee Seung-Jae,Lee He-Jin 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

α-Synuclein is a crucial element in the pathogenesis of Parkinson’s disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence. Transcriptome analysis showed that α-synuclein overexpression led to cellular senescence with activation of the p53 pathway and DNA damage responses (DDRs). Chromatin immunoprecipitation analyses using p53 and γH2AX, chromosomal markers of DNA damage, revealed that these proteins bind to promoters and regulate the expression of DDR and cellular senescence genes. Cellular marker analyses confirmed cellular senescence and the accumulation of DNA double-strand breaks. The non-homologous end joining (NHEJ) DNA repair pathway was activated in α-synuclein-overexpressing cells. However, the expression of MRE11, a key component of the DSB repair system, was reduced, suggesting that the repair pathway induction was incomplete. Neuropathological examination of α-synuclein transgenic mice showed increased levels of phospho-α-synuclein and DNA double-strand breaks, as well as markers of cellular senescence, at an early, presymptomatic stage. These results suggest that the accumulation of DNA double-strand breaks (DSBs) and cellular senescence are intermediaries of α-synuclein-induced pathogenesis in PD.

Heterogeneity in liver histopathology is associated with GSK-3β activity and mitochondrial dysfunction in end-stage diabetic rats on differential diets

( Jun-ho Lee ),( Soo-bong Choi ),( Dong-jun Sung ),( Mingli Jin ),( Ju-han Lee ),( Ji-young Mun ),( Tae-sook Hwang ),( Sang-don Han ),( Young-tae Ro ),( Sung-young Kim ),( Jueng-soo You ),( Inja Lim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2020 BMB Reports Vol.53 No.2

While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague- Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorierestricted (18R group), and 11 were both calorie- and proteinrestricted with the low-protein diet (6R group). Overnightfasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state. [BMB Reports 2020; 53(2): 100-105]

Establishment of active chromatin structure at enhancer elements by mixed-lineage leukemia 1 to initiate estrogen-dependent gene expression

Jeong, Kwang Won,Andreu-Vieyra, Claudia,You, Jueng Soo,Jones, Peter A.,Stallcup, Michael R. Oxford University Press 2014 Nucleic acids research Vol.42 No.4

<P>A number of genome-wide analyses have revealed that estrogen receptor α binding to and regulation of its target genes correlate with binding of FOXA1, a pioneer factor, to nearby DNA sites in MCF-7 breast cancer cells. The enhancer element-specific histone H3K4me1/2 mark is enriched at the specific FOXA1/ERα recruitment sites in chromatin, but the mechanism by which these enhancer marks are established in chromatin before hormone treatment is unclear. Here, we show that mixed-lineage leukemia 1 (MLL1) protein is a key determinant that maintains permissive chromatin structure of the <I>TFF1</I> enhancer region. MLL1 occupies the <I>TFF1</I> enhancer region and methylates H3K4 before hormone stimulation. <I>In vitro</I>, MLL1 binds directly to the CpG-rich region of the <I>TFF1</I> enhancer, and its binding is dependent on hypomethylation of DNA. Furthermore, the depletion of MLL1 in MCF-7 cells results in a dramatic decrease of chromatin accessibility and recruitment of FOXA1 and ERα to the enhancer element. Our study defines the mechanism by which MLL1 nucleates histone H3K4 methylation marks in CpG-enriched regions to maintain permissive chromatin architecture and allow FOXA1 and estrogen receptor α binding to transcriptional regulatory sites in breast cancer cells.</P>

자작나무에 감작된 소아에서 과일 알레르기를 진단하기 위한 microarray법에 의한 성분 항원검사

최원복 ( Won Bok Choi ),유정섭 ( Jueng Sup You ),이윤영 ( Yoon Young Yi ),정수인 ( Soo In Jeong ),송준섭 ( Joon Sup Song ),양승 ( Seong Yang ),황일태 ( Il Tae Hwang ),이하백 ( Ha Baik Lee ),백혜성 ( Hey Sung Baek ) 대한천식알레르기학회 2015 Allergy Asthma & Respiratory Disease Vol.3 No.3

Purpose: Recently, component-resolved diagnosis (CRD) using microarray technology has been introduced to the field of clinical allergy. This study was aimed to investigate the clinical usefulness of microarray-based IgE detection for diagnosing clinical raw fruit allergy in birch pollen-sensitized children. Methods: Thirty-one children with allergic disease who had been sensitized to pollen were studied. A pollen-sensitized patient was defined as having an allergen-specific history with concomitant positive skin-prick tests (SPTs) to natural allergen extracts or positive allergen-specific IgE. All subjects underwent SPTs for pollen and fruit. In all subjects, specific IgE to pollen and fruit were measured by ImmunoCAP. Specific IgE antibodies to allergen components were determined by a customized allergen microarray (ISAC). Results: Thirteen of the 31 patients (41.9%) had a history of fruit hypersensitivity with positive SPTs. Measuring IgE to allergen components by ISAC, all the 13 patients with fruit hypersensitivity were positive to at least one of Mal d 1, Pru p 1, Pru p 3, Act d 8, and Act d 2 compared to 12 of the 13 patients (92.3%) who had at least 1 positive IgE to fruits (apple, peach, and kiwi) using ImmunoCAP. The sensitivity of ISAC microarray was 100.0% for the diagnosis of fruit hypersensitivity, but its specificity was 27.7% (5/18). The sensitivity of ImmunoCAP was 92.3%, and its specificity was 83.3%. Conclusion: The sensitivity of allergen components tested using microarray for the diagnosis of clinical fruit hypersensitivity in children with pollen allergy was high; however, its specificity was low.(Allergy Asthma Respir Dis 2015;3:200-205)

Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis

Lee, Seung Jun,Gharbi, Amal,You, Jueng Soo,Han, Hee Dong,Kang, Tae Heung,Hong, Seong Hwi,Park, Won Sun,Jung, In Duk,Park, Yeong-Min Elsevier 2019 INTERNATIONAL IMMUNOPHARMACOLOGY Vol.73 No.-

<P><B>Abstract</B></P> <P>There is currently no specific drug for the treatment of sepsis and antibiotic administration is considered the best option, despite numerous issues. Therefore, the development of drugs to control the pathogen-induced inflammatory responses associated with sepsis is essential. To address this, our study examined the transcriptomes of lipopolysaccharide (LPS)-induced dendritic cells (DCs), identifying TANK-binding kinase1 (Tbk1) as a key factor involved in the inflammatory response. These data suggested drug repositioning of the Tbk1 inhibitor CYT387, currently used for the treatment of myelofibrosis and some cancers, as a candidate for regulating the LPS-induced inflammatory response. CYT387 also inhibited pro-inflammatory cytokine and surface molecule expression by mature DCs after LPS exposure. These effects correlated with both Akt phosphorylation and IκBα degradation. Finally, CYT387 demonstrated therapeutic effects in LPS-induced endotoxemia and <I>Escherichia coli</I> K1-induced mouse models of sepsis and decreased the expression of pro-inflammatory cytokines. In conclusion, our study suggests that drug repositioning of CYT387 may serve as a potential therapeutic for sepsis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Tbk1 is the most relevant kinase in the “dendritic cell maturation” pathway induced by LPS. </LI> <LI> CYT387 inhibits pro-inflammatory gene expression by interfering with the Akt and NF-κB signaling cascades. </LI> <LI> CYT387 prevents organ dysfunction in <I>E. coli</I> K1-induced sepsis and LPS-induced endotoxemia. </LI> </UL> </P>