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姓名:高承福

職稱:副研究員

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專長:Transcription Regulation,
Chromatin Structure & Dynamics

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研究人員 / 簡介
  2006-  Assistant research fellow, Institute of Cellular and Organismic Biology, Academia Sinica
  2005-2006, Research Faculty, Dept. of Molecular and Microbiology, University of New Mexico
  2002-2005, Postdoctoral Research Fellow, Dept. of Molecular and Microbiology, University of New Mexico
  2002, University of  Edinburgh Ph. D,  Biochemistry

高承福 老師 實驗室

  • Summary of Research Interests and Achievements

          My laboratory has focused on functional analyses of histone modifications, centered on the regulation and function of histone H2B ubiquitylation (H2Bub). In the past years, my research group provided new insight into the biological functions of chromatin dynamics regulated by H2Bub. In collaboration with Dr. Didier Devys at the IGBMC, France, we analyzed the H2Bub deubiquitylation activity of SAGA and observed that SAGA acts on the whole transcribed genome in a rapid manner and this highly dynamic association of the complex with chromatin is required for RNA polymerase II transcription (Bonnet et al., 2014). In addition to transcriptional regulation, it has also been shown that H2Bub promotes recovery from replication stress; however, the underlying molecular mechanism remains unclear. We employed a genome-wide approach to investigate how H2Bub affects DNA replication under stress. We observed that coordination of chromatin assembly and DNA damage checkpoint activity by H2Bub is critical for the cell response to replication stress. The replication proteins on replicating DNA are akin to a train on the tracks, and movement of this train is carefully controlled. Our data indicate that H2Bub helps organize DNA in the nuclei during DNA replication; this process plays a similar role to the brakes on a train, serving to slow down replication, and thus maintaining stable progression of replication under environmental stress (Lin et al., 2014). In addition to the molecular function of histone modifications, we recently demonstrate that the expression of Snf1, a member of the AMP-activated protein kinase family is influenced by ubiquitin specific protease Ubp8 and Ubp10, whose best known target is histone H2B (Hsu et al., 2015). In this study we provide evidence the level of Snf1 protein is dramatically decreased in an UBP8 and UBP10 deleted yeast mutant (ubp8D ubp10D), and this is independent of transcriptional regulation and proteasome-mediated degradation. We identified that a novel feedback loop connects Snf1 protein level and its phosphorylation in a manner independent of its ubiquitin-mediated degradation, and this dynamic regulation of Snf1 activity is crucial for adaptation to environmental stress.

    On-going projects:

    H2B ubiquitylation and the Asf1 histone chaperone mediate the formation and maintenance of heterochromatin architecture

          Heterochromatin is a heritable form of gene repression, with critical roles in development and cell identity. Understanding how chromatin structure results in such repression is a fundamental question. Chromatin is assembled and disassembled during transcription, replication, and repair by Anti-silencing function 1 (Asf1), a highly conserved histone chaperone. Transcription and DNA replication are also affected by histone modifications, such as H2B ubiquitylation (H2Bub), which exerts effects on nucleosome dynamics. We report here that H2Bub and Asf1 synergistically maintain transcriptional silencing at yeast telomeres and mating loci. By monitoring silencing establishment at the HML locus in real time, we found that the initiation of transcriptional repression was attenuated and never fully established in a mutant lacking both Asf1 and H2Bub. These findings are consistent with a significant reduction in both the binding of the Sir2 and Sir3 repressor proteins at HML silencers, and spreading of these proteins. In addition, mutants lacking H2Bub and Asf1 show defects in both nucleosome assembly and higher-order heterochromatin organization at the HML locus. Our findings reveal a novel role for H2Bub and Asf1 in epigenetic silencing through promoting nucleosome formation. We propose that nucleosome assembly is an ongoing requirement for the formation and maintenance of heterochromatin.

    H2B mono-ubiquitylation promotes error-free DNA damage tolerance pathways by fine-tuning chromatin structure around replication forks

          DNA lesions bypass is mediated by DNA damage tolerance (DDT) pathways activated by the ubiquitylation of the replication clamp PCNA. However, it is largely unknown how these pathways take action within the context of chromatin. Histone H2B mono-ubiquitylation (H2Bub) has been previously shown to promote nucleosome dynamics during transcription elongation and DNA double strand breaks in yeast or human cells. In our study, we provide evidence that suggests that H2Bub modulates chromatin dynamics and contributes to error-free DDT processes during and after replication. Several lines of evidence support this conclusion. We find that:

    (1) In the absence of H2Bub, MMS-damaged forks are resistant to restart and accompanied with the accumulation of unrepaired ssDNA gaps.

    (2) Both template switch and salvage HR pathways are impaired in a manner that is downstream of the post-modification of PCNA in cells lack of H2Bub.

    (3) Our genetic data support that DNA synthesis during gap repair is dependent on H2Bub.

    (4) H2Bub is epistatic to RAD51 and promotes Rad51 recruitment to DNA damage sites.

    (5) H2Bub is required for promoting chromatin accessibility around damaged forks.

    Taken together, those results point out the importance of chromatin dynamics around replication forks for efficient recruitment of factors to facilitate the DNA damage tolerance pathways and uphold the genome integrity. Our findings are the first to indicate that H2Bub promotes DNA damage tolerance, through the regulation of chromatin configuration. As such, this project will provides a major advance in our understanding of DNA damage tolerance pathways in relationship with chromatin structure.

    Reference

    Bonnet, J., Wang, C.Y., Baptista, T., Vincent, S.D., Hsiao, W.C., Stierle, M., Kao, C.F., Tora, L., and Devys, D. (2014). The SAGA coactivator complex acts on the whole transcribed genome and is required for RNA polymerase II transcription. Genes Dev 28, 1999-2012.

    Hsu, H.E., Liu, T.N., Yeh, C.S., Chang, T.H., Lo, Y.C., and Kao, C.F. (2015). Feedback Control of Snf1 Protein and Its Phosphorylation Is Necessary for Adaptation to Environmental Stress. J Biol Chem 290, 16786-16796.

    Lin, C.Y., Wu, M.Y., Gay, S., Marjavaara, L., Lai, M.S., Hsiao, W.C., Hung, S.H., Tseng, H.Y., Wright, D.E., Wang, C.Y., et al. (2014). H2B Mono-ubiquitylation Facilitates Fork Stalling and Recovery during Replication Stress by Coordinating Rad53 Activation and Chromatin Assembly. PLoS Genet 10, e1004667.

     

     

     

  • 姓名職稱電話Email備註
    高承福副研究員
  •  Publications in peer-reviewed journals in recent 5 years

    (Total citation; 1653 /H-index:15 )

    1. McDonald MJ, Yu YH, Guo JF, Chong SY, Kao CF and Leu JY. Mutation at a distance caused by homopolymericguanine repeats in  Saccharomyces cerevisiae. Sci Adv. 2016 May; 2(5): e1501033.
    2. Hsu HE, Liu TN, Yeh CS, Chang TH, Lo YC, Kao CF*. Feedback control of Snf1 protein and its phosphorylation is necessary for adaptation to environmental stress. J Biol Chem. 2015 Jul 3;290(27):16786-96. doi: 10.1074/jbc.M115.639443. ( ÛCorrespondent author)
    3. Wright DE and Kao CF*. (Ubi)quitin' the h2bit: recent insights into the roles of H2B ubiquitylation in DNA replication and transcription. Epigenetics. 2015 Feb;10(2):122-6. doi: 10.1080/15592294.2014.1003750. ( ÛCorrespondent author) (SCI IF: 5.108; Rank 26 out of 165 journals in GENETICS & HEREDIT, 15.75%).
    4. Lin CY, Wu MY, Gay S, Marjavaara L, Lai MS, Hsiao WC, Hung SH, Tseng HY, Wright DE, Wang CY, Hsu GSW, Devys D, Chabes A and Kao CF*. (2014) H2B mono-ubiquitylation facilitates fork stalling and recovery during replication stress by coordinating Rad53 activation and chromatin assembly. PLoS Genet 10: e1004667. ( ÛCorrespondent author) (SCI IF: 8.167; Rank 14 out of 164 journals in GENETICS & HEREDIT, 8.53%)
    5. Bonnet J*, Wang CY*, Baptista T, Vincent SD, Hsiao WC, Stierle M, Kao CF, Tora L& and DevysD& (2014) The SAGA coactivator complex acts on the whole transcribed genome and is required for RNA polymerase II transcription  Genes Dev. 2014 Sep 15;28(18):1999-2012. doi: 10.1101/gad.250225.114. ( ÛFirst authors; &Correspondent authors) (SCI IF: 12.639; Rank 11 out of 185 journals in CELL BIOLOGY, 5.94%)
    6. Tang CH, Lai YR, Chen YC, Li CH, Lu YF, Chen HY, Lien HW, Yang CH, Huang CJ, Wang CY, Kao CF, Hwang SP. Expression of zebrafish anterior gradient 2 in the semicircular canals and supporting cells of otic vesicle sensory patches is regulated by Sox10. Biochim Biophys Acta. 2014 Jun;1839(6):425-37. doi: 10.1016/j.bbagrm.2014.04.017. (SCI IF: 5.44; Rank 48 out of 291 journals in BIOCHEMISTRY & MOLECULAR BIOLOGY, 16.49%)
    7. Wu CS, Yu CY, Chuang CY, Hsiao M, Kao CF, Kuo HC, Chuang TJ (2014) Integrative transcriptome sequencing identifies trans-splicing events with important roles in human embryonic stem cell pluripotency. Genome Res. 2014 Jan;24(1):25-36. doi: 10.1101/gr.159483.113. (SCI IF: 14.397; Rank 6 out of 290 journals in BIOCHEMISTRY & MOLECULAR BIOLOGY, 2.06%)
    8. Lin CY, Hsiao WC, Huang CJ, Kao CF* and Hsu GS W* (2013) Heme oxygenase-1 induction by the ROS-JNK pathway plays a role in aluminum-induced anemia. J Inorg Biochem. 2013 Nov;128:221-8. ( ÛCorrespondent authors) (SCI IF: 3.197; Rank 10 out of 43 journals in CHEMISTRY, INORGANIC & NUCLEAR, 23.25%)
    9. Hou PS, Chuang CY, Kao CF, Chou SJ, Stone L, Ho HN, Chien CL, Kuo HC (2013) LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1. Nucleic Acids Res. 2013 Jun 26 [Epub ahead of print]. (SCI IF: 8.278; Rank 27 out of 290 journals in BIOCHEMISTRY & MOLECULAR BIOLOGY, 9.31%)
    10. Lin CY, Hsiao WC, Wright DE, Hsu CL, Lo YC, Wang-Hsu GS and Kao CF* (2013) Resveratrol activates the histone H2B ubiquitin ligase, RNF20, in MDA-MB-231 breast cancer cells. J Funct Foods 2013 5 (2): 790-800. ( ÛCorrespondent author) (SCI IF: 2.632; Rank 20 out of 124 journals in FOOD SCIENCE & TECHNOLOGY, 16.12%)
    11. Lee CL, Hsiao WC, Wright DE, Chong SY, Leow SK, Ho CT, Kao CF and Lo YC (2013) Induction of GADD45a expression contributes to the anti-proliferative effects of polymethoxyflavones on colorectal cancer cells. J Funct Foods 2013 5 (2): 616-624. (SCI IF: 2.632; Rank 20 out of 124 journals in FOOD SCIENCE & TECHNOLOGY, 16.12%)
    12. Wright DE, Wang CY, Kao CFÛ (2012). Histone ubiquitylation and chromatin dynamics. Front Biosci. 2012 Jan 1;17:1051-78. (ÛCorrespondent author) (SCI IF: 4.408; Rank 83 out of 286 journals in BIOCHEMISTRY & MOLECULAR BIOLOGY, 29.02%)
    13. Shieh GS, Pan CH, Wu JH, Sun YJ, Wang CC, Tung L, Chang TH, Fleming AB, Hillyer C, Lo YC, Berger SL, Osley MA* and Kao CF* (2011). H2B ubiquitylation is part of chromatin architecture that marks exon-intron structure in budding yeast. BMC Genomics. 2011 Dec 22;12:627  ( ÛCorrespondent authors) (SCI IF: 4.206; Rank 24 out of 160 journals in BIOTECHNOLOGY & APPLIED MICROBIOLOGY, 15%)
    14. Wright D.E, Wang CY, Kao CFÛ (2011). Flickin’ the Ubiquitin Switch: The Role of H2BUbiquitylation in Development. Epigenetics. 2011 Oct 1;6 (10) (ÛCorrespondent author) (SCI IF: 4.622; Rank 66 out of 286 journals in BIOCHEMISTRY & MOLOCULAR BIOLOGY, 23.07%).
    15. Wang CY, Hua CY, Hsu HE, Hsu CL, Tseng HY, Wright DE, Hsu PH, Jen CH, Lin CY, Wu MY, Tsai MD and Kao CFÛ (2011). The C-terminus of histone H2B is involved in chromatin compaction specifically at telomeres, independently of its monoubiquitylation at lysine 123. PLoS ONE 6(7): e22209. doi:10.1371 /journal.pone.0022209 ( ÛCorrespondent author) (SCI IF: 4.411; Rank 12 out of 86 journals in BIOLOGY, 13.95%)
    16. Cheng PY, Lin YP, Chen YL, Lee YC, Tai CC, Wang YT, Chen YJ, Kao CFÛ and Yu JÛ (2011). Interplay between SIN3A and STAT3 mediates chromatin conformational changes and GFAP expression during cellular differentiation. PLoS ONE 6(7): e22018. doi:10.1371/journal.pone.0022018 (ÛCorrespondent authors) (SCI IF: 4.411; Rank 12 out of 86 journals in BIOLOGY, 13.95%).
    17. Lu TY*, Kao C F*, Lin CT, Huang DY, Chiu CY and Wu, HC (2009) DNA methylation and histone modification regulate silencing of osteoprotegerin during tumor progression. J Cell Biochem. Sep 1;108(1):315-25. (*co-first authors)
    18. Hwang YC, Lu TY, Huang DY, Kuo YS, Kao CF, Yeh NH, Wu HC*, and Lin CT (2009). NOLC1, an enhancer for NPC progression, is essential for TP53 to regulate MDM2 expression. Am J Pathol Jul; 175(1): 342-354.
    19. Fleming AB, Kao CF, Hillyer C, Pikaart M and Mary Ann Osley (2008): H2B ubiquitylation plays a role in nucleosome dynamics during transcription elongation.  Mol Cell. 2008 Jul 11;31(1):57-66.
    20. Kao CF, Chuang CY, Chen CH and Kuo HC. (2008): Human Pluripotent Stem Cells: Current Status and Future Perspectives. Chin J Physiol 51(4): 214-225
    21. Osley, MA, Fleming, AB, and Kao, CF (2006): Histone ubiquitylation and the regulation of transcription, "Chromatin Dynamics in Cellular Function", Results Probl Cell Differ. 2006;41:47-75. ed. B. Laurent, Springer-Verlag (Heidelberg).
    22. Xiao T*, Kao CF*, Sun Z-W, Osley MA, and. Strahl BD. (2005). Histone H2B ubiquitylation is associated with elongating RNA polymerase II.  Mol Cell Biol. 2005 Jan;25(2):637-51 (* co-first authors).
    23. Kao CF, Hillyer C, Tsukuda T, Henry K, Berger S, Osley MA. (2004). Rad6 plays a role in transcriptional activation through ubiquitylation of histone H2B.  Genes Dev. 18(2):184-95.
    24. Henry, K., Wyce, A., Lo, W.-S., Duggan, L., Emre, T., Kao, CF, Pillus, L., Shilatifard, A., Osley, M.A., and    Berger, S.L. (2003).  Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8.  Genes Dev. 17(21):2648-63
    25. Meehan, R., Kao, CF., and Pennings, S. (2003).  HP1 binding to native chromatin in vitro is determined by the hinge region and not the chromodomain.  EMBO J. 22: 3164-3174.
    26. Kao, CF and Osley, M.A. (2003).  In vivo assays to study histone ubiquitylation.  Methods 31: 59-66.

     


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    115台北市南港區研究院路二段128號
    Tel: 02-27899515
    Fax: 02-27858059
    icob@gate.sinica.edu.tw
    Copyright © ICOB 2013. All rights reserved. 最佳瀏覽網頁方式請用最新版IE11或其他瀏覽器 /瀏覽人數:914268--
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