1. Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia 22908-0733, USA

Correspondence to: C. David Allis Correspondence and requests for materials should be addressed to C.D.A. (e-mail: Email: allis@virginia.edu).

Abstract

In eukaryotes, the DNA of the genome is packaged with histone proteins to form nucleosomal filaments, which are, in turn, folded into a series of less well understood chromatin structures¹. Post-translational modifications of histone tail domains modulate chromatin structure and gene expression^{2, 3, 4}. Of these, histone ubiquitination is poorly understood. Here we show that the ubiquitin-conjugating enzyme Rad6 (Ubc2) mediates methylation of histone H3 at lysine 4 (Lys 4) through ubiquitination of H2B at Lys 123 in yeast (Saccharomyces cerevisiae). Moreover, H3 (Lys 4) methylation is abolished in the H2B-K123R mutant, whereas H3-K4R retains H2B (Lys 123) ubiquitination. These data indicate a unidirectional regulatory pathway in which ubiquitination of H2B (Lys 123) is a prerequisite for H3 (Lys 4) methylation. We also show that an H2B-K123R mutation perturbs silencing at the telomere, providing functional links between Rad6-mediated H2B (Lys 123) ubiquitination, Set1-mediated H3 (Lys 4) methylation, and transcriptional silencing. Thus, these data reveal a pathway leading to gene regulation through concerted histone modifications on distinct histone tails. We refer to this as 'trans-tail' regulation of histone modification, a stated prediction of the histone code hypothesis^{5, 6}.