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Negative Regulation of Hypoxic Responses via Induced Reptin Methylation
Lee, Jason S.,Kim, Yunho,Kim, Ik Soo,Kim, Bogyou,Choi, Hee June,Lee, Ji Min,Shin, Hi-Jai R.,Kim, Jung Hwa,Kim, Ji-Young,Seo, Sang-Beom,Lee, Ho,Binda, Olivier,Gozani, Or,Semenza, Gregg L.,Kim, Minhyung Elsevier 2010 Molecular cell Vol.39 No.1
<P><B>Summary</B></P><P>Lysine methylation within histones is crucial for transcriptional regulation and thus links chromatin states to biological outcomes. Although recent studies have extended lysine methylation to nonhistone proteins, underlying molecular mechanisms such as the upstream signaling cascade that induces lysine methylation and downstream target genes modulated by this modification have not been elucidated. Here, we show that Reptin, a chromatin-remodeling factor, is methylated at lysine 67 in hypoxic conditions by the methyltransferase G9a. Methylated Reptin binds to the promoters of a subset of hypoxia-responsive genes and negatively regulates transcription of these genes to modulate cellular responses to hypoxia.</P> <P><B>Highlights</B></P><P>► Reptin is a target of G9a methyltransferase ► Reptin K67 methylation is induced by hypoxia ► Genome-wide identification of hypoxia target genes negatively regulated by Reptin ► Hypoxia-driven Reptin methylation negatively regulates tumorigenic behavior in vivo</P>
Jinkwon Kim,Junsik Mun,Youngdo Kim,Bongju Kim,Jeong Rae Kim,Lingfei Wang,Miyoung Kim,Changyoung Kim,Jason W. A. Robinson,Yoshiteru Maeno,Tae Won Noh 한국자기학회 2021 한국자기학회 학술연구발표회 논문개요집 Vol.31 No.2
Ruddlesden-Popper (RP) phase oxides (An+1BnO3n+1, n = 1, 2, ...) have been spotlighted with versatile physical properties such as high-temperature superconductivity, colossal magnetoresistance. These emergent phenomena provide a platform for novel oxide-based electronic devices including spintronics application. However, high-quality RP-phase thin film growth has been disturbed by extended structural defects, such as out-of-phase boundaries (OPBs). OPB is a translational boundary between neighboring unit cells, shifted in a specific crystallographic direction. For instance, if RP-phase thin films grown on ABO₃ perovskite substrates, the structural mismatch between film and substrates induces a crystallographic shift in the c-axis direction, thus OPBs form at the film-substrate interface. Since OPB formation hampers the physical properties of RP-phase thin films, the suppression of the structural defects is highly required to carry out the high-performance RP-phase based functional devices. In this study, we suppressed OPB suppression in RP-phase oxide thin films by atomic-scale interface engineering. As model systems, the unconventional superconductor Sr₂RuO₄ (bulk Tc ~ 1.5 K) and La2-xSrxCuO₄ (bulk Tc ~ 39 K) thin films were employed. Despite the structural similarities between films and substrates, Sr2RuO4 and La2-xSrxCuO₄ films exhibited huge OPB formations. By controlling the atomic-scale interface engineering, the OPBs were significantly suppressed in the film structure. Notably, these OPB-free Sr₂RuO₄ and La2-xSrxCuO₄ thin films exhibited highly enhanced superconductivity than the film with huge OPB formation. Our study suggests a comprehensive method to suppress OPB formation in RP thin films, enabling superconducting spintronics devices based on the unconventional superconductivity.
EZH2 Generates a Methyl Degron that Is Recognized by the DCAF1/DDB1/CUL4 E3 Ubiquitin Ligase Complex
Lee, J.,Lee, Jason S.,Kim, H.,Kim, K.,Park, H.,Kim, J.Y.,Lee, S.,Kim, I.,Kim, J.,Lee, M.,Chung, C.,Seo, S.B.,Yoon, J.B.,Ko, E.,Noh, D.Y.,Kim, K.,Kim, K.,Baek, S. Cell Press 2012 Molecular cell Vol.48 No.4
Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing ''methyl degron''; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.
Kim, Jason Y.,Cheong, Hyun Sub,Park, Byung-Lae,Baik, Sei Hyun,Park, Sunmin,Kim, Seogho,Shin, Hyoung Doo,Kim, Sung-Hoon Informa UK Ltd. 2013 Gynecological endocrinology Vol.29 No.10
<P>We hypothesized that <I>ubiquitin-conjugating enzyme E2 E2</I> (<I>UBE2E2</I>) may be associated with gestational diabetes mellitus (GDM) and conducted association analyses. A total of 2071 subjects were recruited for the study, with 1104 cases and 967 controls. Two <I>UBE2E2</I> single-nucleotide polymorphisms <I>rs6780569</I> and <I>rs7612463</I>, and their haplotypes were analyzed for the study. As a result, <I>rs7612463</I> showed a significant association with GDM in the recessive model. In addition, the regression analyses for the phenotypes showed that <I>rs6780569. rs7612463</I> and <I>ht2</I> showed significant associations with fasting plasma glucose (FPG) in recessive models, while <I>ht1</I> showed an association in the dominant model. Our results show that the genetic variants of <I>UBE2E2</I> are associated with GDM and FPG, which could be an important preliminary result for future studies.</P>
Kim, Jung Hwa,Lee, Ji Min,Nam, Hye Jin,Choi, Hee June,Yang, Jung Woo,Lee, Jason S,Kim, Mi Hyang,Kim, Su-Il,Chung, Chin Ha,Kim, Keun Il,Baek, Sung Hee National Academy of Sciences 2007 Proceedings of the National Academy of Sciences Vol.104 No.52
<P>Posttranslational modification by small ubiquitin-like modifier (SUMO) controls diverse cellular functions of transcription factors and coregulators and participates in various cellular processes including signal transduction and transcriptional regulation. Here, we report that pontin, a component of chromatin-remodeling complexes, is SUMO-modified, and that SUMOylation of pontin is an active control mechanism for the transcriptional regulation of pontin on androgen-receptor target genes in prostate cancer cells. Biochemical purification of pontin-containing complexes revealed the presence of the Ubc9 SUMO-conjugating enzyme that underlies its function as an activator. Intriguingly, 5alpha-dihydroxytestosterone treatments significantly increased the SUMOylation of pontin, and SUMOylated pontin showed further activation of a subset of nuclear receptor-dependent transcription and led to an increase in proliferation and growth of prostate cancer cells. These data clearly define a functional model and provide a link between SUMO modification and prostate cancer progression.</P>
Kim, Jason Yongha,Kim, Ho Jin,Cheong, Hyun Sub,Bae, Joon Seol,Kim, Jeong-Hyun,Park, Byung Lae,Shin, Hyoung Doo Edition Medizin 2013 Neuro endocrinology letters Vol.34 No.5
<P>This study was conducted to find the possible association between CD226 polymorphisms and inflammatory demyelinating diseases in Korean population.</P>
Kim, Jason Yongha,Kim, Jeong-Hyun,Park, Byung-Lae,Pasaje, Charisse Flerida A.,Bae, Joon Seol,Uh, Soo-Taek,Kim, Yong-Hoon,Kim, Mi-Kyeong,Choi, Inseon S.,Cho, Sang Heon,Choi, Byoung Whui,Park, Jong Sook Informa Healthcare 2012 The Journal of asthma Vol.49 No.3
<P><I>Background.</I> The <I>discoidin domain receptor tyrosine kinase 1</I> (<I>DDR1</I>) is positioned within the major histocompatibility complex (MHC) region which plays an important role in the immune system. In addition, DDR1 has been elucidated to be downregulated during the epithelial-mesenchymal transition of bronchial epithelium. <I>Objective.</I> To investigate the potential genetic associations between <I>DDR1</I> and aspirin-exacerbated respiratory disease (AERD), this study conducted association studies of <I>DDR1</I> single nucleotide polymorphisms (SNPs) with AERD and the obstructive symptom of forced expiratory volume in 1 s (FEV<SUB>1</SUB>) decline after aspirin provocation. <I>Methods.</I> Nine common SNPs were genotyped in 93 AERD patients and 96 aspirin-tolerant asthma (ATA) controls. The genotype distributions of all loci were in Hardy-Weinberg equilibrium (HWE; <I>p</I> > .05). <I>Results.</I> In the results of logistic analyses using age, sex, smoking status, and atopy as covariates, <I>DDR1 rs1264320</I> in the intronic region showed a potent association signal with FEV<SUB>1</SUB> decline by aspirin provocation in asthmatics of this study even after corrections for multiple testing (<I>p</I> == .003 and corrected <I>p</I> == .01). However, the variants of <I>DDR1</I> were not significantly associated with the AERD development (corrected <I>p</I> > .05). On further comparison of FEV<SUB>1</SUB> decline by aspirin provocation between AERD and ATA, the variant <I>rs1264320</I> was found to be associated with the FEV<SUB>1</SUB> decline of ATA rather than AERD. <I>Conclusion.</I> Despite the need for further functional evaluations and replications, we conclude that <I>DDR1</I> polymorphisms are not likely to contribute to predispositions of AERD, but may be potentially associated with FEV<SUB>1</SUB> decline by aspirin provocation in asthmatics.</P>
Putative association of <i>SMAPIL</i> polymorphisms with risk of aspirin intolerance in asthmatics
Yongha Kim, Jason,Kim, Jeong-Hyun,Park, Byng-Lae,Sub Cheong, Hyun,Sook Park, Jong,Soo Jang, An,Uh, Soo-Taek,Choi, Jae-Sung,Kim, Yong-Hoon,Kim, Mi-Kyeong,Choi, Inseon S.,Heon Cho, Sang,Whui Choi, Byoun Informa Healthcare 2010 The Journal of asthma Vol.47 No.9
<P><I>Background.</I> Aspirin-intolerant asthma (AIA), as a clinical syndrome caused by aspirin, is characterized by lung inflammation and reversible bronchoconstriction. Recently, the altered trafficking and diminished airway reactivity have been implicated in allergic airway remodeling. The stromal membrane-associated protein 1-like (SMAP1L) exerts common and distinct functions in vesicle trafficking including endocytosis. The disturbance of pulmonary surfactant synthesis has been elucidated to be associated with asthma experimentally. Moreover, in alveolar type II (ATII) cells that synthesize pulmonary surfactant, alterations of clathrin-dependent endocytosis cause disturbance at the surfactant function, suggesting that SMAP1L, which directly interacts with clathrin, could be associated with asthma and related phenotypes. <I>Objective.</I> To verify our hypothesis that <I>SMAP1L</I> could play a role in the development of AIA, this study investigated associations between single-nucleotide polymorphisms (SNPs) of the <I>SMAP1L</I> gene and AIA. <I>Methods.</I> We conducted an association study between 19 SNPs of the <I>SMAP1L</I> gene and AIA in a total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of <I>SMAP1L</I> and AIA were analyzed with sex, smoking status, atopy, and body mass index as covariates. <I>Results.</I> Logistic analyses revealed that three common polymorphisms, <I>rs2982510</I>, <I>rs2294752</I>, and <I>rs446738</I>, were putatively associated with the increased susceptibility to AIA (<I>p</I> = .003, <I>p</I><SUP>corr</SUP> = .004, OR = 0.24, 95% CI = 0.09-0.62 for <I>rs2982510</I> and <I>rs2294752</I>; <I>p</I> = .008, <I>p</I><SUP>corr</SUP> = .03, OR = 0.44, 95% CI = 0.24-0.80 for <I>rs446738</I>, in the recessive model). In addition, <I>rs2982510</I> and <I>rs2294752</I> were significantly associated with the fall of forced expiratory volume in 1 s (FEV<SUB>1</SUB>) by aspirin provocation (<I>p</I> = .001, <I>p</I><SUP>corr</SUP> = .04 in the recessive model for both SNPs). <I>Conclusions.</I> Our findings suggest that <I>SMAP1L</I> might be a susceptible gene to AIA, providing a new strategy for the control of aspirin intolerance.</P>