Microfluidic Gut-liver chip for reproducing the first pass metabolism

Choe, Aerim,Ha, Sang Keun,Choi, Inwook,Choi, Nakwon,Sung, Jong Hwan Springer-Verlag 2017 Biomedical microdevices Vol.19 No.1

Regulation of MDM2 E3 ligase-dependent vascular calcification by MSX1/2

권덕화,Choe Nakwon,신세라,Ryu Juhee,김낙성,Eom Gwang Hyeon,Nam Kwang-Il,Kim Hyung Seok,Ahn Youngkeun,김영국,Park Woo Jin,Mendrysa Susan M.,Kook Hyun 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

Vascular calcification increases morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we reported that histone deacetylase 1 prevents vascular calcification, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), induces vascular calcification. In the present study, we identified the upstream regulator of MDM2. By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. By promoter analysis, we found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the MDM2 promoter region, which resulted in transcriptional activation of MDM2. The expression levels of both Msx1 and Msx2 were increased in mouse models of vascular calcification and in calcified human coronary arteries. Msx1 and Msx2 potentiated vascular calcification in cellular and mouse models in an MDM2-dependent manner. Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification.

Regulation of Acetylation of Histone Deacetylase 2 by p300/CBP-Associated Factor/Histone Deacetylase 5 in the Development of Cardiac Hypertrophy

Eom, Gwang Hyeon,Nam, Yoon Seok,Oh, Jae Gyun,Choe, Nakwon,Min, Hyun-Ki,Yoo, Eun-Kyung,Kang, Gaeun,Nguyen, Vu Hong,Min, Jung-Joon,Kim, Jong-Keun,Lee, In-Kyu,Bassel-Duby, Rhonda,Olson, Eric N.,Park, Woo Grune & Stratton 2014 Circulation research Vol.114 No.7

<P><B><U>Rationale:</U></B></P><P>Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of class I and class IIa HDACs are well established, the significance of interclass crosstalk in the development of cardiac hypertrophy remains unclear.</P><P><B><U>Objective:</U></B></P><P>Recently, we suggested that casein kinase 2α1–dependent phosphorylation of HDAC2 leads to enzymatic activation, which in turn induces cardiac hypertrophy. Here we report an alternative post-translational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor/HDAC5.</P><P><B><U>Methods and Results:</U></B></P><P>Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. Acetylation was reduced by a histone acetyltransferase inhibitor but was increased by a nonspecific HDAC inhibitor. The enzymatic activity of Hdac2 was positively correlated with its acetylation status. p300/CBP-associated factor bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress–induced acetylation. The acetylation-resistant Hdac2 K75R showed a significant decrease in phosphorylation on S394, which led to the loss of intrinsic activity. Hdac5, one of class IIa HDACs, directly deacetylated Hdac2. Acetylation of Hdac2 was increased in Hdac5-null mice. When an acetylation-mimicking mutant of Hdac2 was infected into cardiomyocytes, the antihypertrophic effect of either nuclear tethering of Hdac5 with leptomycin B or Hdac5 overexpression was reduced.</P><P><B><U>Conclusions:</U></B></P><P>Taken together, our results suggest a novel mechanism by which the balance of HDAC2 acetylation is regulated by p300/CBP-associated factor and HDAC5 in the development of cardiac hypertrophy.</P>

Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling

Nam, Yoon Seok,Kim, Yoojung,Joung, Hosouk,Kwon, Duk-Hwa,Choe, Nakwon,Min, Hyun-Ki,Kim, Yong Sook,Kim, Hyung-Seok,Kim, Don-Kyu,Cho, Young Kuk,Kim, Yong-Hoon,Nam, Kwang-Il,Choi, Hyoung Chul,Park, Dong H American Heart Association, Inc. 2014 Circulation research Vol.115 No.5

<P><B><U>Rationale</U>:</B></P><P>Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA-binding domain. Through interactions with other transcription factors, SHP regulates diverse biological events, including glucose metabolism in liver. However, the role of SHP in adult heart diseases has not yet been demonstrated.</P><P><B><U>Objective</U>:</B></P><P>We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy.</P><P><B><U>Methods and Results</U>:</B></P><P>The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP-null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of hypertrophy in cardiomyocytes. SHP reduced the protein amount of Gata6 and, by direct physical interaction with Gata6, interfered with the binding of Gata6 to GATA-binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an antidiabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced antihypertrophic effect was attenuated either by SHP small interfering RNA in cardiomyocytes or in SHP-null mice.</P><P><B><U>Conclusions</U>:</B></P><P>These results establish SHP as a novel antihypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced antihypertrophic response.</P>

Enhancer of polycomb1 acts on serum response factor to regulate skeletal muscle differentiation.

Kim, Ju-Ryoung,Kee, Hae Jin,Kim, Ji-Young,Joung, Hosouk,Nam, Kwang-Il,Eom, Gwang Hyeon,Choe, Nakwon,Kim, Hyung-Suk,Kim, Jeong Chul,Kook, Hoon,Seo, Sang Beom,Kook, Hyun American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.24

<P>Skeletal muscle differentiation is well regulated by a series of transcription factors. We reported previously that enhancer of polycomb1 (Epc1), a chromatin protein, can modulate skeletal muscle differentiation, although the mechanisms of this action have yet to be defined. Here we report that Epc1 recruits both serum response factor (SRF) and p300 to induce skeletal muscle differentiation. Epc1 interacted physically with SRF. Transfection of Epc1 to myoblast cells potentiated the SRF-induced expression of skeletal muscle-specific genes as well as multinucleation. Proximal CArG box in the skeletal alpha-actin promoter was responsible for the synergistic activation of the promoter-luciferase. Epc1 knockdown caused a decrease in the acetylation of histones associated with serum response element (SRE) of the skeletal alpha-actin promoter. The Epc1.SRF complex bound to the SRE, and the knockdown of Epc1 resulted in a decrease in SRF binding to the skeletal alpha-actin promoter. Epc1 recruited histone acetyltransferase activity, which was potentiated by cotransfection with p300 but abolished by si-p300. Epc1 directly bound to p300 in myoblast cells. Epc1+/- mice showed distortion of skeletal alpha-actin, and the isolated myoblasts from the mice had impaired muscle differentiation. These results suggest that Epc1 is required for skeletal muscle differentiation by recruiting both SRF and p300 to the SRE of muscle-specific gene promoters.</P>

Sumoylation of histone deacetylase 1 regulates MyoD signaling during myogenesis

Joung, Hosouk,Kwon, Sehee,Kim, Kyoung-Hoon,Lee, Yun-Gyeong,Shin, Sera,Kwon, Duk-Hwa,Lee, Yeong-Un,Kook, Taewon,Choe, Nakwon,Kim, Jeong Chul,Kim, Young-Kook,Eom, Gwang Hyeon,Kook, Hyun Nature Publishing Group 2018 Experimental and molecular medicine Vol.50 No.1

<P>Sumoylation, the conjugation of a small ubiquitin-like modifier (SUMO) protein to a target, has diverse cellular effects. However, the functional roles of the SUMO modification during myogenesis have not been fully elucidated. Here, we report that basal sumoylation of histone deacetylase 1 (HDAC1) enhances the deacetylation of MyoD in undifferentiated myoblasts, whereas further sumoylation of HDAC1 contributes to switching its binding partners from MyoD to Rb to induce myocyte differentiation. Differentiation in C2C12 skeletal myoblasts induced new immunoblot bands above HDAC1 that were gradually enhanced during differentiation. Using SUMO inhibitors and sumoylation assays, we showed that the upper band was caused by sumoylation of HDAC1 during differentiation. Basal deacetylase activity was not altered in the SUMO modification-resistant mutant HDAC1 K444/476R (HDAC1 2R). Either differentiation or transfection of SUMO1 increased HDAC1 activity that was attenuated in HDAC1 2R. Furthermore, HDAC1 2R failed to deacetylate MyoD. Binding of HDAC1 to MyoD was attenuated by K444/476R. Binding of HDAC1 to MyoD was gradually reduced after 2 days of differentiation. Transfection of SUMO1 induced dissociation of HDAC1 from MyoD but potentiated its binding to Rb. SUMO1 transfection further attenuated HDAC1-induced inhibition of muscle creatine kinase luciferase activity that was reversed in HDAC1 2R. HDAC1 2R failed to inhibit myogenesis and muscle gene expression. In conclusion, HDAC1 sumoylation plays a dual role in MyoD signaling: enhancement of HDAC1 deacetylation of MyoD in the basally sumoylated state of undifferentiated myoblasts and dissociation of HDAC1 from MyoD during myogenesis.</P>