Regulatory mechanism of chromatin accessibility by Dot1 (Disruptor of Telomere silencing 1) in Saccharomyces cerevisiae

Abstract

Dot1 (disruptor of telomeric silencing-1, DOT1L in human) is the only enzyme required to histone H3 lysine 79 methylation (H3K79me), and evolutionarily conserved in most eukaryotes. Although Dot1p is well-known to participate in the regulation of gene silencing near telomeres via H3 K79 methylation in Saccharomyces cerevisiae, it is unclear the reason why H3 K79 methylation is highly distributed in most euchromatic genes, and the role and molecular mechanism of Dot1p in euchromatin. Here I show that Dot1p regulate chromatin accessibility via histone exchange without methyltransferase activity in yeast. Dot1p preferentially binds euchromatin region that is demarcated by histone H4 Lysine 16 acetylation (H4K16ac) which encodes open chromatin structure. I find that a novel function of Dot1p independent of histone methylation is required for cryptic transcriptions within transcribed regions in mutants of Set2-Rpd3S pathway genes. Also, Dot1p increases histone exchange in transcribed regions. Indeed, Dot1p is able to assemble core histones and nucleosome, and facilitates ATP-dependent chromatin remodeling activity through its nucleosome binding domain in vitro. Global analysis indicates that Dot1p appears to be particularly important in histone exchange and chromatin accessibility on the transcribed regions of long genes. Together with H3K79me activity of Dot1p, my study proposes Dot1p contributes to the regulation of transcription in euchromatin via chromatin accessibility regulation mechanism.