Structural basis for the regulation of nucleosome recognition and HDAC activity by histone deacetylase assemblies

Abstract

The chromatin-modifying histone deacetylases (HDACs) remove acetyl groups from acetyl-lysine residues in histone amino-terminal tails, thereby mediating transcriptional repression. Structural makeup and mechanisms by which multisubunit HDAC complexes recognize nucleosomes remain elusive. Our cryo–electron microscopy structures of the yeast class II HDAC ensembles show that the HDAC protomer comprises a triangle-shaped assembly of stoichiometry Hda12-Hda2-Hda3, in which the active sites of the Hda1 dimer are freely accessible. We also observe a tetramer of protomers, where the nucleosome binding modules are inaccessible. Structural analysis of the nucleosome-bound complexes indicates how positioning of Hda1 adjacent to histone H2B affords HDAC catalysis. Moreover, it reveals how an intricate network of multiple contacts between a dimer of protomers and the nucleosome creates a platform for expansion of the HDAC activities. Our study provides comprehensive insight into the structural plasticity of the HDAC complex and its functional mechanism of chromatin modification.

Hda1C restricts the transcription initiation frequency to limit divergent non-coding RNA transcription

“…We note that our analyses failed to identify the equivalent effects in the respective mutants, perhaps most notably a statistically significant increase of initiation frequency was limited to hda3∆. While the differences may be rooted in differential effects of the Hda1C components (Lee et al, 2021), we favor the hypothesis that some effects may be masked by experimental variation and the modest effect size. Hda1C selectively deacetylates histones H2B and H3 (Carmen et al, 1996).…”

Opposing functions of the Hda1 complex and histone H2B mono-ubiquitylation in regulating cryptic transcription inSaccharomyces cerevisiae

“…The second, independently derived suppressor mutation identified in our screen, sup2-23 , is a nonsense mutation at codon 198 of HDA3 . Structural studies indicate that the regions deleted by the sup2-22 and sup2-23 mutations encompass a coiled-coil segment necessary for dimeric interactions between Hda2 and Hda3, which are required for the overall integrity and function of Hda1C ( Wu et al 2001a ; Lee et al 2009 , 2021 ). We asked whether suppression of the rtf1 mutations was specific to our original hda3 mutations or whether loss of any subunit within Hda1C could confer suppression.…”

“…Our results demonstrate that absence of a functional Hda1C suppresses the cryptic initiation and telomeric silencing phenotypes of certain rtf1 HMD mutants. To test if loss of Hda1C catalytic activity could similarly suppress the rtf1-108-110A mutation, we mutated an invariant histidine, H206, in the catalytic center of Hda1 and introduced this hda1-H206A mutation at the endogenous HDA1 locus by allelic replacement ( Lee et al 2021 ). For both the cryptic initiation and telomeric silencing phenotypes, the hda1-H206A mutation largely phenocopied the hda1Δ mutation with respect to rtf1 suppression ( Figure 2A ).…”

Targeting HDACs of apicomplexans: structural insights for a better treatment

“…Therefore, we were unable to model some of these proteins' regions since they have many insertions with unknown function and structure. The Saccharomyces cerevisiae HDACs have a C-terminal coiled-coil domain that functions as a scaffold for the HDAC complex, an evidence that the insertion regions may play a similar role in the Apicomplexa (Lee et al ., 2021). We suggest more in vitro studies on these proteins should be conducted.…”