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

Lee, Jung‐Hoon; Bollschweiler, Daniel; Schäfer, Tillman; Huber, Robert

doi:10.1126/sciadv.abd4413

Cited by 24 publications

(17 citation statements)

References 51 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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).…”

Section: Discussionmentioning

confidence: 65%

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

Gowthaman

Ivanov

Schwarz

et al. 2021

Preprint

View full text Add to dashboard Cite

Nucleosome-depleted regions (NDRs) at gene promoters support initiation of RNA Polymerase II transcription. Interestingly, transcription often initiates in both directions, resulting in an mRNA, and a divergent non-coding (DNC) transcript with an unclear purpose. Here, we characterized the genetic architecture and molecular mechanism of DNC transcription in budding yeast. We identified the Hda1 histone deacetylase complex (Hda1C) as a repressor of DNC in high-throughput reverse genetic screens based on quantitative single-cell fluorescence measurements. Nascent transcription profiling showed a genome-wide role of Hda1C in DNC repression. Live-cell imaging of transcription revealed that Hda1C reduced the frequency of DNC transcription. Hda1C contributed to decreased acetylation of histone H3 in DNC regions, supporting DNC repression by histone deacetylation. Our data support the interpretation that DNC results as a consequence of the NDR-based architecture of eukaryotic promoters, but that it is governed by locus-specific repression to maintain genome fidelity.

show abstract

Section: Discussionmentioning

confidence: 65%

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

Gowthaman

Ivanov

Schwarz

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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 ).…”

Section: Resultsmentioning

confidence: 99%

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

Shirra

Kocik

Ellison

et al. 2021

G3 Genes|Genomes|Genetics

View full text Add to dashboard Cite

Maintenance of chromatin structure under the disruptive force of transcription requires cooperation among numerous regulatory factors. Histone post-translational modifications can regulate nucleosome stability and influence the disassembly and reassembly of nucleosomes during transcription elongation. The Paf1 transcription elongation complex, Paf1C, is required for several transcription-coupled histone modifications, including the mono-ubiquitylation of H2B. In Saccharomyces cerevisiae, amino acid substitutions in the Rtf1 subunit of Paf1C greatly diminish H2B ubiquitylation and cause transcription to initiate at a cryptic promoter within the coding region of the FLO8 gene, an indicator of chromatin disruption. In a genetic screen to identify factors that functionally interact with Paf1C, we identified mutations in HDA3, a gene encoding a subunit of the Hda1C histone deacetylase, as suppressors of an rtf1 mutation. Absence of Hda1C also suppresses the cryptic initiation phenotype of other mutants defective in H2B ubiquitylation. The genetic interactions between Hda1C and the H2B ubiquitylation pathway appear specific: loss of Hda1C does not suppress the cryptic initiation phenotypes of other chromatin mutants and absence of other histone deacetylases does not suppress the absence of H2B ubiquitylation. Providing further support for an appropriate balance of histone acetylation in regulating cryptic initiation, absence of the Sas3 histone acetyltransferase elevates cryptic initiation in rtf1 mutants. Our data suggest that the H2B ubiquitylation pathway and Hda1C coordinately regulate chromatin structure during transcription elongation and point to a potential role for a histone deacetylase in supporting chromatin accessibility.

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

Targeting HDACs of apicomplexans: structural insights for a better treatment

et al. 2022

View full text Add to dashboard Cite

Aetiologic agents of diseases such as malaria and toxoplasmosis are found in representatives of the phylum Apicomplexa. Therefore, apicomplexan parasites are known to have a significant impact on public health. Epigenetic factors such as histone acetylation/deacetylation are among the main mechanisms of gene regulation in these parasites. Histone deacetylases (HDACs) have aroused a great deal of interest over the past 20 years for being promising targets in the development of drugs for treating several diseases such as cancer. In addition, they have also been shown to be effective for parasitic diseases. However, little is known about the structure of these proteins, as well as their interactions with specific ligands. In this paper, we modelled 14 HDACs from different apicomplexan parasites and performed molecular docking with 12 ligands analogous to the HDAC inhibitors FR235222 and apicidin, which had previously been tested against Toxoplasma gondii and Plasmodium falciparum. In this in silico study, we were able to gather relevant structural data regarding these proteins as well as insights into protein–ligand interactions for testing and developing drugs for these diseases.

show abstract

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

Cited by 24 publications

References 51 publications

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

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

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

Targeting HDACs of apicomplexans: structural insights for a better treatment

Contact Info

Product

Resources

About