染色质与表观遗传学系列讲座第21场 – Kristian Helin

发布日期：2021-12-31　　浏览次数：32191

北京时间2022年1月4日（周二） 20:00-21:00

2022 January 4th Tuesday 20:00-21:00 (Beijing Time)

Zoom网络研讨会: 843 6931 3262

Bilibili直播：http://live.bilibili.com/22741871

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Webinar ID: 843 6931 3262

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Kristian Helin

Dr. Kristian Helin is the CEO and President of The Institute of Cancer Research (ICR) in London. He obtained a MSc in Chemical Engineering from the Technical University of Denmark and a PhD from University of Copenhagen. He was a research fellow at Harvard Medical School, started his own research group at the Danish Cancer Society in 1994 and became subsequently a founding member of the Dept of Experimental Oncology at the European Institute of Oncology in Milan, Italy. From 2003 to 2018 he was the founding director of the Biotech Research and Innovation Centre at University of Copenhagen and in 2018-2021 Prof Helin was the Chair of the Cell Biology Program and the Director of Center for Epigenetics Research at Memorial Sloan Kettering Cancer Center, New York. The Helin laboratory has made several seminal discoveries in the field of cell cycle control, epigenetics and cancer. In addition to providing novel insights into mechanisms regulating transcription, stem cell identity and differentiation, the work in Prof Helin’s lab has led to the establishment of the biotech companies EpiTherapeutics and Dania Therapeutics. Dr. Helin is an elected member of European Molecular Biology Organisation (EMBO) and the Royal Danish Academy of Science and Letters. He has received several prestigious awards for outstanding biomedical research and serves in several editorial boards, committees of advisory boards and grant committees.

Kristian Helin教授是伦敦癌症研究所 (ICR) 的首席执行官兼主席。他在丹麦技术大学获得化学工程硕士学位，在哥本哈根大学获得博士学位，之后在哈佛医学院担任研究员。1994年，他在丹麦癌症协会成立了自己的研究组，随后成为意大利米兰欧洲肿瘤研究所实验肿瘤学系的创始成员。2003年至2018年，他是哥本哈根大学生物技术研究与创新中心的创始主任。2018年至2021年，Helin教授担任纪念纽约斯隆凯特琳癌症中心细胞生物学项目主席和表观遗传学研究中心主任。Helin实验室在细胞周期调控、表观遗传学和癌症领域取得了多项开创性发现，对转录、干细胞身份和分化等生物学过程调节机制提供了新的见解。此外，Helin 实验室的工作还促成了生物技术公司EpiTherapeutics和Dania Therapeutics的成立。Helin教授是欧洲分子生物学组织（EMBO）和丹麦皇家科学院的成员。他因杰出的生物医学研究而获得多项著名奖项，并在多个编辑委员会、顾问委员会和资助委员会任职。

Epigenetics and its role in transcriptional control, cell fate and cancer

Cell fate decisions are regulated by an intricate interplay between the cellular environment, growth factors and intracellular signaling pathways. The balance of stability versus plasticity in stem cells is a regulatory challenge, and extensive studies in recent years have focused on understanding the contribution of transcription factors and epigenetic enzymes in the regulation of cellular identity and differentiation pathways. Disruption of epigenetic control is a frequent event in disease, and the first epigenetic-based therapies for cancer treatment have been approved. A generation of new classes of potent and specific inhibitors for several chromatin-associated proteins have shown promise in pre-clinical trials. Although the biology of epigenetic regulation is complex, these and other new inhibitors will hopefully be of clinical use in the coming years.

The research in my lab is focused on understanding the role of epigenetic regulators in maintaining cellular identity and how their deregulation leads to cancer. In the seminar, I will discuss some of our recent results aimed at understanding how chromatin-associated proteins control transcription, contribute to cell fate decisions and how their deregulation can lead to cancer.

1) Radzisheuskaya, A., Shliaha, P. V., Grinev, V. V., Shlyueva, D., Damhofer, H., Koche, R., Gorshkov, V., Kovalchuk, S., Zhan, Y., Rodriguez, K. L., Johnstone, A. L., Keogh, M. C., Hendrickson, R. C., Jensen, O. N., & Helin, K. (2021). Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcription and cellular homeostasis. Molecular cell, 81(8), 1749–1765.e8. https://doi.org/10.1016/j.molcel.2021.02.012

2) Müller, I., Moroni, A. S., Shlyueva, D., Sahadevan, S., Schoof, E. M., Radzisheuskaya, A., Højfeldt, J. W., Tatar, T., Koche, R. P., Huang, C., & Helin, K. (2021). MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells. Nature communications, 12(1), 3034. https://doi.org/10.1038/s41467-021-23308-4

3) Sankar, A., Lerdrup, M., Manaf, A., Johansen, J. V., Gonzalez, J. M., Borup, R., Blanshard, R., Klungland, A., Hansen, K., Andersen, C. Y., Dahl, J. A., Helin, K., & Hoffmann, E. R. (2020). KDM4A regulates the maternal-to-zygotic transition by protecting broad H3K4me3 domains from H3K9me3 invasion in oocytes. Nature cell biology, 22(4), 380–388. https://doi.org/10.1038/s41556-020-0494-z

4) Radzisheuskaya A, Shliaha PV, Grinev V, Lorenzini E, Kovalchuk S, Shlyueva D, Gorshkov V, Hendrickson RC, Jensen ON, Helin K. PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia. Nat Struct Mol Biol. 2019 Nov;26(11):999-1012. doi: 10.1038/s41594-019-0313-z. Epub 2019 Oct 14.

5) Højfeldt JW, Hedehus L, Laugesen A, Tatar T, Wiehle L, Helin K. Non-core Subunits of the PRC2 Complex Are Collectively Required for Its Target-Site Specificity. Mol Cell. 2019 Nov 7;76(3):423-436.e3. doi: 10.1016/j.molcel.2019.07.031. Epub 2019 Sep 11.

6) Rasmussen KD, Berest I, Keβler S, Nishimura K, Simón-Carrasco L, Vassiliou GS, Pedersen MT, Christensen J, Zaugg JB, Helin K. TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells. Genome Res. 2019 Apr;29(4):564-575. doi: 10.1101/gr.239277.118. Epub 2019 Feb 22.

7) Højfeldt J, Laugesen A, Willumsen BM, Damhofer H, Hedehus L, Tvardovskiy A, Mohammad F, Jensen ON & Helin K. Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2. Nature Structural & Molecular Biology. (2018)

8) Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt, JW, Comet I, Zheng C, Johansen JV, Rapin N, Porse BT, Tvardovskiy A, Jensen ON, Olaciregui NG, Lavarino C, Suñol M, de Torres C, Mora J, Carcaboso AM & Helin K. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nature Medicine 4, 483-492, doi: 10.1038/nm.4293 (2017).

9) Agger K, Miyagi S, Pedersen MT, Kooistra SM, Johansen JV & Helin K. Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells. Genes & Development 30, 1278-1288, doi:10.1101/gad.280495.116 (2016).

10) Pedersen MT*, Kooistra SM*, Radzisheuskaya A, Laugesen A, Johansen JV, Hayward DG, Nilsson J, Agger K & Helin K. Continual removal of H3K9 promoter methylation by Jmjd2 demethylases is vital for ESC self-renewal and early development. The EMBO Journal 35, 1550-1564, doi:10.15252/embj.201593317 (2016).

11) Rasmussen KD, Jia G, Johansen JV, Pedersen MT, Rapin N, Bagger FO, Porse BT, Bernard OA, Christensen J & Helin K. Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes & Development 29, 910-922, doi:10.1101/gad.260174.115 (2015).

12) Riising EM, Comet I, Leblanc B, Wu X, Johansen JV & Helin K. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Molecular Cell 55, 347-360, doi: 10.1016/j.molcel.2014.06.005 (2014).

13) Wu X, Johansen JV & Helin K. Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Molecular Cell 49, 1134-1146, doi: 10.1016/j.molcel.2013.01.016 (2013).

14) Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J & Helin K. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature, 473, 343-8.

15) Pasini D, Cloos PA, Walfridsson J, Olsson L, Bukowski JP, Johansen JV, Bak M, Tommerup N, Rappsilber J & Helin K (2010). JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464, 306-310.

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