染色质与表观遗传学系列讲座第17场 –Matthew Lorincz

发布日期：2021-11-08　　浏览次数：13646

北京时间2021年11月9日（周二） 11:00-12:00

2021 November 9th Tuesday 11:00-12:00 (Beijing Time)

Zoom网络研讨会: 843 6931 3262

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Matthew Lorincz

Dr. Matthew Lorincz is professor and interim head of Department of Medical Genetics, University of British Columbia. He obtained his bachelor's degree from the University of California, Berkeley in 1990 and obtained his PhD in 1997 from Stanford University School of Medicine. During 1997 to 2003, Dr. Lorincz worked as postdoctoral fellow supervised by Dr. David Martin and Dr. Mark Groudine in Fred Hutchinson Cancer Research Center in Seattle, and became staff scientist there in 2003. He started working in University of British Columbia as assistant professor in 2005 and became full professor in 2015. His lab studies the role of histone modifications, DNA methylation, and chromatin remodeling factors in transcriptional regulation of genes and retroelements during mouse development using next-generation sequencing technologies.

Matthew Lorincz教授是加拿大英属哥伦比亚大学医学遗传学系的教授和临时负责人。他于1990年在加州大学伯克利分校获得学士学位，1997年在斯坦福大学医学院获得博士学位。1997年至2003年间，他在西雅图弗雷德·哈钦森癌症研究中心担任博士后研究员，分别在David Martin教授和Mark Groudine教授的实验室工作，并在2003年成为该中心的研究员。2005他开始在加拿大英属哥伦比亚大学工作，担任助理教授，并于2015年成为正教授。他的实验室使用新一代测序技术研究组蛋白修饰、DNA 甲基化和染色质重塑因子在小鼠发育过程中基因和逆转录因子转录调控中的作用。

Chromatin-guided DNA methylation: Insights from the mouse germline & early embryo

DNA methylation (DNAme) is highly dynamic during mammalian development, including “global" waves of de novo DNA methylation that take place in the germline and in the early embryo. In the first half of the talk, I will discuss the sexually dimorphic patterns of DNAme observed in male versus female gametes, and the underlying molecular basis of the difference. While de novo DNAme in oocytes requires the lysine methyltransferase (KMTase) SETD2, which deposits the histone post-translational modification (PTM) H3K36me3, we find that this KMTase is dispensable for global DNAme in prospermatogonia (PSG), including at paternally imprinted regions. Rather an alternative H3K36 KMTase, NSD1, is required for directing de novo DNAme in quiescent PSG, including at H3K27me3 marked regions and paternally imprinted loci. I will discuss the role of NSD1 in safeguarding a subset of genes against H3K27me3-associated transcriptional silencing and compare the phenotype of NSD1 cKO PSG to that of Dnmt3l deficient PSG. In the second half of the talk, I will discuss the chromatin factors/complexes involved in the transcriptional repression in pre- and post-implantation embryos of a set of germline genes involved in “genome defense”, including PRC1.6, SETDB1 and the de novo DNA methyltransferases. I will present the order of events in which the marks deposited by these factors, H2AK119ub1, H3K9me3 and DNAme respectively, are deposited in embryogenesis, and the crosstalk between them, as determined using ESC lines deficient in specific chromatin factors and the naïve (n)ESC-EpiLC differentiation system. Taken together, these studies reveal the complex interplay between covalent histone modifications and DNAme, with clear implications for the underlying basis of neurodevelopmental disorders and cancers in which these chromatin factors are mutated.

1) Mochizuki K*; Sharif, J; Shirane K*, Uranishi, K, Bogutz, A*; Sanne Janssen*; Suzuki A; Okuda, A; Koseki, H; Lorincz, M. Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing. Nature Communications, Accepted (2021).

2) Gurbet, K; Chan, D; Shirane, K*; McClatchie, T; Janssen, S*; Lorincz, M; and Trasler, J. Paternal MTHFR deficiency leads to reproductive decline across two successive generations in association with hypomethylation of young retrotransposons. Development. 148(13): 1-14 (2021).

3) Martin, B; Brind’Amour*, J; Kuzmin, A; Jenssen, K*; Liu, Z; Lorincz, M and Howe, L. Transcription shapes genome-wide histone acetylation patterns. Nature Communications. 12(1): 1-9 (2021).

4) Janssen S*, Lorincz, MC. Nature Reviews Genetics, https://doi.org/10.1038/s41576-021-00416-x, (2021).

5) Lismer, A; Dumeaux, V; Lafleur, C; Lambrot, R; Brind’Amour*, J; Lorincz, M; Kimmins, S. Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Developmental Cell. 12: 1-9 (2021).

6) Chi-Kuo Hu, Wei Wang, Julie Brind’Amour*, Param Priya Singh, G. Adam Reeves, Matthew C. Lorincz, Alejandro Sánchez Alvarado, Anne Brunet. Vertebrate diapause preserves organisms long term through Polycomb complex members. Science. 367(6480): 870-874 (2020).

7) Julie Brind’Amour* and Matthew C. Lorincz. Setting the chromatin stage in oocytes. Nature Cell Biology. 16: 1-3 (2020).

8) Rebollo R, Galvão-Ferrarini M, Gagnier, L, Zhang Y, Ferraj A, Beck C, Lorincz MC, Mager, DL. Inter-strain epigenomic profiling reveals a candidate IAP master copy in C3H mice. Viruses. 12(783): 1-17 (2020).

9) Shirane K*, Miura F, Ito T, Lorincz MC. NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing. Nature Genetics. 52(10): 1-31 (2020).

10) Yeung W, Brind’Amour J*, Hatano Y, Yamagata K, Feil R, Lorincz M, Tachibana M, Shinkai Y, Sasaki H. Histone H3K9 Methyltransferase G9a in Oocytes Is Essential for Preimplantation Development but Dispensable for CG Methylation Protection. Cell Reports. 27(1): 282-293 (2019).

11) Bogutz A*, Brind’Amour J*, Kobayashi H, Jensen K*, Nakabayashi K, Imai H, Lorincz M, Lefebvre L. Endogenous retroviruses direct the evolution of lineage-specific imprinting. Nature Communications. 10: 1-14 (2019).

12) Xu, Q, Xiang, Y Wang Q, et al., Brind’Amour J*, Bogutz A*, Walker C, Jonasch E, Lefebvre L, Wu M, Lorincz M, Li W, Li L, Xie W. SETD2 regulates maternal epigenomic reprogramming and fertility. Nature Genetics. 51(5): 844-856 (2019).

13) Hui Shi, Ruslan Strogantsev, Nozomi Takahashi, Anastasiya Kazachenka , Matthew C. Lorincz, Myriam Hemberger and Anne C. Ferguson-Smith. ZFP57 regulation of transposable elements and gene expression within and beyond imprinted domains. Epigenetics & Chromatin. 12(49): 1-13 (2019).

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