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Pavel HOZAK – Nuclear phosphoinositides: new players in gene expression

Nuclear phosphoinositides: new players in gene expression

Professor Pavel HOZAK,

Institute of Molecular Genetics,

Prague, Czech Republic,

Invité par Yegor Vassetzky

Processes such as gene expression or DNA repair are compartmentalized within eukaryotic nucleus, and nuclear environment contains dynamic membrane-less sub-compartments whose formation is prevalently driven by phase separation. It Apparently, formation of phase boundaries provides the surface for spatiotemporal control contributing to the high-rate kinetics of crucial processes such as transcription, ribosome maturation, splicing. I will briefly recapitulate the history of my research and devote a majority of my talk to recent findings from our Prague laboratory. findings We discovered the Nuclear Lipid Islets (NLIs) – globular ~100 nm structures containing PI(4,5)P2 (PIP2) at their periphery which associate with key transcription factors, and showed that NLIs are crucial for efficient Polymerase II transcription. To decipher whether the NLIs surface recruits a transcription regulatory proteins through PIP2 molecules in their surface, we employed a proteomic approach based on differential quantitative mass in combination with super-resolution microscopy. We identified more than 300 NLIs-associated proteins belonging to gene expression (53%) and pre-mRNA splicing (33%). Super-resolution microscopy confirmed that some candidate proteins form foci in nucleoplasm and associate with sub-population of NLIs. Further, our bioinformatical analysis of putative NLIs proteins revealed that majority of them contain Intrinsically Disordered Regions (IDRs). IDRs are known features of proteins undergoing phase separation under in vivo and in vitro conditions. Moreover, we found that the vast majority of these proteins contain K/R rich motifs, which were previously shown as recognition sites for phosphoinositide (PIPs) binding. We hypothesize that NLIs may serve as a structural platform integrating RNA Polymerase II transcription and pre-mRNA splicing by attracting proteins which are prone to form liquid-like particles.

Prof. Pavel Hozak graduated at Moscow State University, accomplished his PhD studies at the Charles University in Prague, and continued his research on the connection between nuclear structure and gene expression as a post-doc at the Dunn School of Pathology in Oxford, UK, and also at the Jacques Monod Institute in Paris, INRA Jouy-en-Josas, and at the Vienna University. From 2006 till now, he is leading the Laboratory of Biology of the Cell Nucleus at the Institute of Molecular Genetics of the Czech Academy of Sciences in Prague, and from 2007, he is a full professor at the Charles University. He actively participated in forming the national and European imaging infrastructure, and from 2012, he serves as the director of Czech-BioImaging National Infrastructure for Biological and Medical Imaging. He published 178 original articles cited >5600x. Besides other awards, he received recently the prestigious Wilhelm Bernhard Medal, and became an honorary member of the Italian Histochemical Society.