BET family members Bdf1/2 modulate global transcription initiation and elongation in Saccharomyces cerevisiae.

Rafal Donczew,Steven Hahn

doi:10.7554/elife.69619

Abstract

Human bromodomain and extra-terminal domain (BET) family members are promising targets for therapy of cancer and immunoinflammatory diseases, but their mechanisms of action and functional redundancies are poorly understood. Bdf1/2, yeast homologues of the human BET factors, were previously proposed to target transcription factor TFIID to acetylated histone H4, analogous to bromodomains that are present within the largest subunit of metazoan TFIID. We investigated the genome-wide roles of Bdf1/2 and found that their important contributions to transcription extend beyond TFIID function as transcription of many genes is more sensitive to Bdf1/2 than to TFIID depletion. Bdf1/2 co-occupy the majority of yeast promoters and affect preinitiation complex formation through recruitment of TFIID, Mediator, and basal transcription factors to chromatin. Surprisingly, we discovered that hypersensitivity of genes to Bdf1/2 depletion results from combined defects in transcription initiation and early elongation, a striking functional similarity to human BET proteins, most notably Brd4. Our results establish Bdf1/2 as critical for yeast transcription and provide important mechanistic insights into the function of BET proteins in all eukaryotes.

Highlights

Bromodomains (BDs) are reader modules that allow protein targeting to chromatin via interactions with acetylated histone tails
Our work reveals that the roles of yeast bromo and extra-terminal (BET) factors are surprisingly similar to their human equivalents and suggests conserved mechanisms of BET function across eukaryotes. 403 Bdf1 was proposed to act as part of yeast TFIID, substituting for the metazoan Taf1 BDs 404 (Matangkasombut et al, 2000)
Transcription from most genes defined earlier as coactivator-redundant (CR) is largely insensitive to Bdf depletion, while a large subset of TFIID-dependent genes is significantly more affected by Bdf vs TFIID depletion. 413 Genome-wide mapping revealed that Bdf1/2 are found together with TFIID at many promoters and 414 that they contribute to TFIID recruitment

Summary

Introduction

Bromodomains (BDs) are reader modules that allow protein targeting to chromatin via interactions with acetylated histone tails. Both of these functions are required to support cell growth and transcription at several loci Based on these findings, it was proposed that Bdf double BD substitutes for the missing BDs of yeast Taf, linking yeast TFIID to promoter-enriched chromatin marks (Matangkasombut et al, 2000; Matangkasombut and Buratowski, 2003). At many genes, the Bdfs regulate transcription elongation and this role contributes to the strong defects in mRNA synthesis upon Bdf depletion These striking functional similarities with mammalian BET factors suggest broad conservation of BET function in eukaryotes

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