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Mardi 21 Mai 2024
Centre de recherche - Paris - Amphithéâtre Constant-Burg - 12 rue Lhomond, Paris 5e

Nucleosomes and DNA methylation – implications for immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome and cancers

DNA methylation is a broadly observed epigenetic modification. As genomic DNA methylation profiles dynamically change during development and aging, alterations in DNA methylation patterns are linked to diseases such as cancers and immunodeficiency. ICF syndrome is characterized by hypomethylation at heterochromatin. Of four proteins whose mutation cause ICF syndromes (DNMT3B, ZBTB24, CDCA7 and HELLS), we have previously demonstrated that CDCA7 is a critical activator for the nucleosome remodeling activity of the SNF2-family ATPase HELLS. As DNA methyltransferases cannot directly methylate DNA on the nucleosome, we suggested that the CDCA7-HELLS complex assists DNA methyltransferases by sliding DNA on the nucleosome. However, it remained unclear why the CDCA7-HELLS complex, among several SNF2-family proteins that can remodel nucleosomes, plays a unique role in DNA methylation. Here, I will share our efforts to fill this gap by showing that CDCA7 is an adaptor for hemimethylated CpG. Implications of this finding for diseases will be discussed.


Hironori Funabiki
Professor, Head of Laboratory

The Rockefeller University, New York

Invité(e)(s) par

Nicolas Manel

Institut Curie

Daniele Fachinetti

Institut Curie

Séminaire proposé par Nicolas Manel

En bref

Hironori Funabiki obtained bachelor of science at Kyoto University in 1990. He then joined Prof. Mitsuhiro Yanagida’s lab in Department of Biophysics at Kyoto University as a PhD student to study chromosome organization and segregation using fission yeast. Applying FISH, he found that centromeres are clustered at the spindle pole body in the nucleus. He also demonstrated that timely degradation of Cut2 protein (now known as securin) is critical for sister chromatid separation. After obtaining PhD in 1995, and one year extension as a postdoc at Kyoto University, in 1996 he joined Prof. Andrew Murray’s lab at UCSF, where he learned the Xenopus egg extract system and developed a method to isolate metaphase chromosomes and anaphase chromosomes. Using this method, he identified the chromokinesin Xkid as a protein critical for pushing chromosomes at the equator. As Prof. Murray moved his lab from UCSF to Harvard University in 2000, he also moved to Harvard until 2002, when he started his own lab at the Rockefeller University as an Assistant Professor. He was promoted to Associate Professor in 2007, and to Professor with tenure in 2014. Since 2002, he has also adjunct Tri-Institutional appointments at Sloan Kettering Institute and Weill Cornell Medicine. At the Rockefeller University, he delineated mechanisms and principles by which chromatin-associated factors control assembly and disassembly of macromolecular architectures, such as spindle, nuclear envelope, and heterochromatin. Through this, his lab demonstrated the importance of the nucleosome as a platform to trigger spindle assembly and nuclear pore complex formation, in part through dissecting the mechanism by which the protein kinase Aurora B is regulated by nucleosomes and microtubules. He also demonstrated that HELLS and CDCA7, whose mutation causes Immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, form a novel nucleosome remodeling complex to facilitate DNA methylation. Additionally, he has discovered that cytoplasmic sensor cGAS, previously known to promote inflammation in response to exposure of viral/bacterial DNA to the cytoplasm, can be inactivated by nucleosomes. Most recently, he developed a new cryo-EM analysis pipeline to determine the high-resolution nucleosome structures formed in functional chromosomes. He was named Searle Scholar in 2002, The Irma T. Hirschl/Monique Weill-Caulier Trust Research Award and Alexandrine and Alexander Sinsheimer Fund Scholar Award in 2003, NIH, NIGMS, Maximizing Investigators' Research Award in 2019 and The Rockefeller University Teaching Award in 2022. He has been a member of editorial board for the Journal of Cell Biology since 2005, and for Open Biology since 2016.