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Our Research

Post-translational modifications of histone proteins are epigenetic mechanisms, which regulate many nuclear processes, including gene transcription and genome maintenance. Misregulation of histone modifying enzyme function is often associated with human developmental disorders and cancer. Small molecules inhibiting histone modifying enzymes or targeting proteins that bind histone modifications (so called ‘epidrugs’) are a potential new class of therapeutics for treating cancers. Our overall research objective is to understand the function and dynamic regulation of histone modifications. Specifically, our focus is to understand the enzymes and regulatory processes involved in the trans-histone crosstalk between histone H2B monoubiquitination and histone H3 lysine-4 (H3K4) and lysine-79 (K79) methylation.

Understanding the function and dynamic regulation of histone H2B ubiquitination

Ubiquitination of histone H2B at lysine-120 (human) or lysine-123 (budding yeast) is connected to gene transcription, and it is also implicated in other nuclear processes, including DNA replication and repair. H2B monoubiquitination is catalyzed by a multi-protein complex comprised of an E2 ubiquitin-conjugating enzyme (yeast Rad6/human HR6A and HR6B), E3 ligases (yeast Bre1/human RNF20 and RNF40) and auxiliary proteins (yeast Lge1/human WAC). Ubiquitin conjugated onto histone H2B is removed by deubiquitinases (DUBs): yeast Ubp8 and Ubp10/ human USP22 and USP12. In trans-histone crosstalk evolutionarily conserved from yeast to humans, H2B monoubiquitination regulates histone H3K4 and K79 methylation mediated by yeast Set1 (human Set1A/Set1B) and yeast Dot1 (human DOT1L), respectively. Enzymes and regulatory factors involved in the dynamic regulation of H2B ubiquitination are mutated or overexpressed in many cancers. By employing classical and modern tools of chromatin biology/epigenetics and using yeast and mammalian model systems, our research will address the following major questions:

a)   How are the enzymes involved in the addition or removal of H2B monoubiquitination assembled, recruited and regulated?

b)   How does H2B monoubiquitination contribute to nucleosomal interactions, to other histone modifications and to nuclear processes in general?

c)   How does the H2B monoubiquitination pathway function in cancer formation and progression?