Factor and histone covalent modifications in genome regulation

Abstract

Genome structure and function is regulated in part via covalent post-translational modifications (PTMs) of histones, including acetylation (ac), methylation (me), phosphorylation (ph), ubiquitylation (ub), and sumoylation (su). Our research focuses on patterns and temporal sequences of PTMs during transcription and sporulation. In transcriptional regulation recent studies examine roles of histone H3 Ser10ph, H2B K123ub, and H2B/H4su. We find that, on one hand, H3 Ser10ph prevents the binding of certain corepressor complexes from binding to histones, and on the other hand, it promotes the binding of several novel transcriptional coactivator molecules. Thus, Ser10ph has an interesting dual role in transcriptional regulation. Secondly, we find that ub/deub of H2B K123 regulates transcriptional elongation by directly regulating histone binding of a RNA polymerase II kinase, Ctk1. Ctk1 binding, in turn, establishes a balance of H3 K4me vs. K36me in the ORF. Hence, K123ub has a unique attribute among histone PTMs: it must be both added and then removed for full transcriptional activation. Finally, we identify H2B/H4su as the first known negative histone modification in S. cerevisiae. The sumo mark appears to block certain positive marks such as acetylation and ubiquitylation. We also study H4 Ser1ph during both S. cerevisiae sporulation and metazoan spermatogenesis. H4Ser1ph persists after the decline of H3 Ser10ph, the well-known mitotic/meiotic modification involved in chromosome condensation. Our results suggest that H4 Ser1ph is involved in chromatin compaction during late stages of sporulation.