Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability

Abstract

Compact chromatin is closely linked with gene silencing in part by sterically masking access to promoters, inhibiting transcription factor binding and preventing polymerase from efficiently transcribing a gene. Here, we propose a broader view: chromatin compaction can be both a cause and a consequence of the histone modification state, and this tight bidirectional interaction can underpin bistable transcriptional states. To test this theory, we developed a mathematical model for the dynamics of the HMR locus in S. cerevisiae, that incorporates activating histone modifications, silencing proteins and a dynamic, acetylation-dependent, three-dimensional locus size. Chromatin compaction enhances silencer protein binding, which in turn feeds back to remove activating histone modifications, leading to further compaction. The bistable output of the model was in good agreement with prior quantitative data, including switching rates from expressed to silent states, and vice versa, and protein binding levels within the locus. We then tested the model by predicting changes in switching rates as the genetic length of the locus was increased, which were then experimentally verified. This bidirectional feedback between chromatin compaction and the histone modification state may be an important regulatory mechanism at many loci. SignificanceChromatin is the complex formed by proteins, including histones, and DNA to form chromosomes. Specific chromatin structures and states are thought to be key factors regulating transcription. A common view proposes that histone modifications activate or inhibit transcription either via specific activation or inhibition of RNA polymerase binding/elongation at a locus, or by expanding/compacting the locus, thereby modulating its accessibility to many macromolecules. In this work, we elucidated a broader hypothesis that chromatin compaction may both inhibit transcription, and feedback via silencing proteins to remove histone modifications that further control chromatin compaction and correlate with gene activity. We developed a model incorporating these ideas and showed that it explains quantitative experimental data for a silent locus in budding yeast.