RNF20 AND USP44 REGULATE STEM CELL DIFFERNTIATION BY MODULATING H2B MONOUBIQUITYLATION

Gilad Fuchs ¹ Efrat Shema ¹ Rita Vesterman ² Eran Kotler ¹ Zohar Wolchinsky ⁴ Lior Golomb ¹ Ariel Pribluda ³ Mahmood Haj-Yahya ⁵ Ashraf Brik ⁵ Jacob Hanna ³ Daniel Aberdam ⁴ Eytan Domany ² Moshe Oren ¹

¹Molecular Cell Biology, Weizmann Institute of Science, Rehovot
²Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot
³Department of Molecular Genetics, Weizmann Institute of Science, Rehovot
⁴INSERTECH, Bruce Rappaport Institute of the Technion, Technion, Haifa
⁵Department of Chemistry, Ben Gurion University of the Negev, Beer Sheva

Embryonic stem cells (ESCs) maintain high genomic plasticity, which is essential for their capacity to enter diverse differentiation pathways. Posttranscriptional modifications of chromatin histones play a pivotal role in maintaining this plasticity. We now report that one such modification, monoubiquitylation of histone H2B on lysine 120 (H2Bub1), catalyzed by the E3 ligase RNF20, increases during ESC differentiation and is required for efficient execution of this process. This increase is particularly important for the transcriptional induction of relatively long genes during ESC differentiation. Furthermore, we identify the deubiquitinase USP44 as a negative regulator of

H2B ubiquitylation, whose downregulation during ESC differentiation contributes to the increase in H2Bub1. Our findings suggest that optimal ESC differentiation requires dynamic changes in H2B ubiquitylation patterns, which must occur in a timely and well-coordinated manner.