Enhancer of Polycomb1, a Novel Homeodomain Only Protein-binding Partner, Induces Skeletal Muscle Differentiation

Kee, Hae Jin; Kim, Ju‐Ryoung; Nam, Kwang Il; Park, Hye Young; Shin, Sera; Kim, Jeong Chul; Shimono, Yohei; Takahashi, Masahide; Jeong, Myung Ho; Kim, Nacksung; Kim, Kyung Keun; Kook, Hyun

doi:10.1074/jbc.m611198200

Cited by 62 publications

(60 citation statements)

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“…Interestingly, histone deacetylase inhibitors have been reported to activate apoptotic pathways including Fas-mediated apoptosis [52][53][54][55] and exhibit therapeutic potential in the treatment of cancer [56,57] and inflammatory diseases [58,59]. In skeletal muscle cells, Hopx is expressed as well, but acts independently of SRF and mostly activates transcription of the target genes [60]. In those cells, enhancer of polycomb 1 has been identified as a novel interaction partner of Hopx [60].…”

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confidence: 99%

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Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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Th1 cells are prominent in inflamed tissue, survive conventional immunosuppression, and are believed to play a pivotal role in driving chronic inflammation. Here, we identify homeobox only protein (Hopx) as a critical and selective regulator of the survival of Th1 effector/memory cells, both in vitro and in vivo. Expression of Hopx is induced by T-bet and increases upon repeated antigenic restimulation of Th1 cells. Accordingly, the expression of Hopx is low in peripheral, naïve Th cells, but highly up-regulated in terminally differentiated effector/memory Th1 cells of healthy human donors. In murine Th1 cells, Hopx regulates the expression of genes involved in regulation of apoptosis and survival and makes them refractory to Fas-induced apoptosis. In vivo, adoptively transferred Hopxdeficient murine Th1 cells do not persist. Consequently, they cannot induce chronic inflammation in murine models of transfer-induced colitis and arthritis, demonstrating a key role of Hopx for Th1-mediated immunopathology.Key words: Cell survival . CD4 T cells . Inflammation . Memory cells Supporting Information available onlineIntroduction T-helper type 1 (Th1) cells mediate immune responses to intracellular pathogens, such as viruses, and produce IFN-g as their signature cytokine [1]. IFN-g, together with IL-12 and the transcription factors STAT1, STAT4 and T-bet, promotes the development of Th1 cells [2][3]. T-bet (T-box 21) is considered to act as the master transcription factor critically regulating Th1 lineage commitment [3][4][5]. Apart from their protective role in clearing infections, Th1 cells can initiate and maintain chronic inflammatory diseases, e.g. inflammatory bowel disease [6][7][8][9], uveitis [10], EAE [11,12] and arthritis [13]. In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Eur. J. Immunol. 2010. 40: 2993-3006 DOI 10.1002 HIGHLIGHTS 2993 FrontlineFas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells. Hopx regulates Fas-mediated apoptosis of effector/memory Th1 cells and is critically required for their persistence in vivo.In vertebrates, Hopx expression originally was detected in the myocardium [27,28]. There, expression of Hopx is induced by the cardiac transcription factor Nkx2-5. Hopx-deficient mice show a complex, incompletely penetrant phenotype. Some Hopxdeficient embryos have a poorly developed myocardium with reduced cell numbers, others show normal, and still others show increased numbers of cardiomyocytes after birth [27,28]. Hopx does not bind to homeobox consensus binding sequences, and it has been postulated that Hopx acts indirectly, partnering with ...

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confidence: 99%

“…In skeletal muscle cells, Hopx is expressed as well, but acts independently of SRF and mostly activates transcription of the target genes [60]. In those cells, enhancer of polycomb 1 has been identified as a novel interaction partner of Hopx [60]. In Th1 cells, Hopx regulates expression of a limited number of genes.…”

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confidence: 99%

Persistence of effector memory Th1 cells is regulated by Hopx

et al. 2010

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“…An interaction between Epc1 and RFP in testis was established in a previous report. 13 We found in this study that RFP is abundant in skeletal muscle, where Epc1 is also highly expressed, 16 and that the interaction between RFP and Epc1 takes place in skeletal myoblast cells. These findings led us to postulate that the interaction may have a biological function in skeletal muscles.…”

Section: Discussionmentioning

confidence: 51%

“…The expression of was also increased by serum deprivation as previously described. 16 Interestingly, the expression of Rfp was downregulated during the differentiation of C2C12 cells ( Figure 2a) and in primary cultured myoblasts (Figure 2b).…”

Section: Resultsmentioning

confidence: 94%

“…Epc1 antibody was described previously. 16 Antibodies were used to recognize MyoD (C-20, Sc-304), myogenin (M-225, Sc-576), skeletal a-actin (Alpha sr-1, Sc-58671), MHC3 (embryonic myosin, Sc-53091), Gapdh (Sc-32233) (all of the above were from Santa Cruz Biotechnology (Santa Cruz, CA, USA)), desmin (ab6322; Abcam, Cambridge, UK), wheat germ agglutinin (W11261, Invitrogen, Eugene, OR, USA), and RFP (#01-8791; American Research Products, Inc., Belmont, MA, USA). H9c2, Cos7, 293T, and C2C12 cells were obtained from the Korean Cell Line Bank (KCLB, Seoul, Korea) and were maintained with DMEM containing 10 or 15% fetal bovine serum for C2C12 cells (growth medium).…”

Section: Methodsmentioning

confidence: 99%

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Ret finger protein inhibits muscle differentiation by modulating serum response factor and enhancer of polycomb1

et al. 2011

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Skeletal myogenesis is precisely regulated by multiple transcription factors. Previously, we demonstrated that enhancer of polycomb 1 (Epc1) induces skeletal muscle differentiation by potentiating serum response factor (SRF)-dependent muscle gene activation. Here, we report that an interacting partner of Epc1, ret finger protein (RFP), blocks skeletal muscle differentiation. Our findings show that RFP was highly expressed in skeletal muscles and was downregulated during myoblast differentiation. Forced expression of RFP delayed myoblast differentiation, whereas knockdown enhanced it. Epc1-induced enhancements of SRF-dependent multinucleation, transactivation of the skeletal a-actin promoter, binding of SRF to the serum response element, and muscle-specific gene induction were blocked by RFP. RFP interfered with the physical interaction between Epc1 and SRF. Muscles from rfp knockout mice (Rfp À/À ) mice were bigger than those from wild-type mice, and the expression of SRF-dependent muscle-specific genes was upregulated. Myotube formation and myoblast differentiation were enhanced in Rfp À/À mice. Taken together, our findings highlight RFP as a novel regulator of muscle differentiation that acts by modulating the expression of SRFdependent skeletal muscle-specific genes. Skeletal muscle is critical for the generation of active force, the maintenance of posture, and body shape. Muscle regeneration from myoblasts is important for the repair and maintenance of skeletal muscles after muscle injury or dystrophy. Myogenesis from the precursor cells to the skeletal muscle lineage consists of multiple steps, and each of these steps is tightly organized by extrinsic and intrinsic signaling pathways. Thus, not only for understanding the regeneration of injured skeletal muscles, but also for furthering therapeutic approaches to muscle atrophy, a hot issue in current research is how the proliferation and differentiation of myoblasts are regulated. To ultimately provide important clues for therapeutics, a comprehensive understanding of how various signaling mechanisms collaborate to regulate the gene expression and epigenetic programs for myoblast differentiation is needed.The TRIM (tripartite motif) protein family (also known as the RBCC protein family) has the common structures of three zinc-binding domains, a RING, a B-box type 1, and a B-box type 2, followed by a coiled-coil region.

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Gene Expression Profiles of Treatment Response and Non‐Response in Children With Juvenile Dermatomyositis

Stingl

Dvergsten

Eng

et al. 2022

ACR Open Rheumatology

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Objective The study objective was to identify differences in gene expression between treatment responders (TRs) and treatment non‐responders (TNRs) diagnosed with juvenile dermatomyositis (JDM). Methods Gene expression analyses were performed using whole blood messenger RNA sequencing in patients with JDM (n = 17) and healthy controls (HCs; n = 10). Four analyses were performed (A1‐4) comparing differential gene expression and pathways analysis exploiting the timing of sample acquisition and the treatments received to perform these comparative analyses. Analyses were done at diagnosis and follow‐up, which averaged 7 months later in the cohort. Results At diagnosis, the expression of 10 genes differed between TRs and TNRs. Hallmark and canonical pathway analysis revealed 11 and 60 pathways enriched in TRs and 3 and 21 pathways enriched in TNRs, respectively. Pathway enrichment at diagnosis in TRs was strongest in pathways involved in metabolism, complement activation, and cell signaling as mediated by IL‐8, p38/microtubule associated protein kinases (MAPK)/extracellular signal‐regulated kinases (ERK), Phosphatidylinositol 3 Kinase Gamma (PI3Kγ), and the B cell receptor. Follow‐up hallmark and canonical pathway analysis showed that 2 and 14 pathways were enriched in TRs, whereas 24 and 123 pathways were enriched in treatment TNRs, respectively. Prior treatment with glucocorticoids significantly altered expression of 13 genes in the analysis of subjects at diagnosis with JDM as compared with HCs. Conclusion Numerous genes and pathways differ between TRs and TNRs at diagnosis and follow‐up. Prior treatment with glucocorticoids prior to specimen acquisition had a small effect on the performed analyses.

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Enhancer of Polycomb1, a Novel Homeodomain Only Protein-binding Partner, Induces Skeletal Muscle Differentiation

Cited by 62 publications

References 37 publications

Persistence of effector memory Th1 cells is regulated by Hopx

Persistence of effector memory Th1 cells is regulated by Hopx

Ret finger protein inhibits muscle differentiation by modulating serum response factor and enhancer of polycomb1

Gene Expression Profiles of Treatment Response and Non‐Response in Children With Juvenile Dermatomyositis

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