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HEIndividual fellowship2022–2024

HDACbyCRYOEM · High-resolution cryo-EM structures of the human and yeast Sin3 histone deacetylase complexes

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2022-10-01 → 2024-09-30
EU contribution
€191,760
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

High-resolution cryo-EM structures of the human and yeast Sin3 histone deacetylase complexes

Histone deacetylase (HDAC) complexes are the main transcriptional repression machineries in eukaryotes. Their disruption leads to gene expression deregulations and causes numerous diseases, involving cancers, inflammatory diseases, and neurological disorders. The 11 promiscuous HDAC enzymes in human have thus been widely exploited to study fundamental transcription-related mechanisms and deliver small-molecule therapeutics, including five HDAC-inhibiting drugs that have been approved by the US Food and Drug Administration (FDA) . Owing to their lack of specificity and toxicity in vivo, current HDAC inhibitors have been limited to the treatment of haematological cancers. However, HDAC complexes are made of multiple other protein subunits that are poorly characterized. Better understanding of HDAC complex biology would thus lead to the development of more specific inhibitors and treatments focused on alternative protein targets. In this context, the absence of complete, high-resolution 3D structures for the whole SIN3 HDAC machineries has hindered the precise understanding and validation of how small molecules can perturb the overall architecture of the complexes to reprogram their biological functions. This has also precluded chemical optimizations of the initial molecules and design of novel compounds targeting different proteins. In this application, we proposed to combine the expertise of the applicant in HDAC complex biology and druggability, to that of his supervisor in structural biology and cryo-EM to solve the structures of: 1) the human SIN3A HDAC complex [specific aim 1], and 2) the highly-conserved yeast S. cerevisiae Sin3/Rpd3L HDAC complex [specific aim 2], at near atomic resolution, by single-particle cryogenic electron microscopy (cryo-EM).

Data: CORDIS, © European Union

Project objective

Histone deacetylase (HDAC) complexes are the main transcriptional repression machineries in eukaryotes. Disruption of their functions can lead to various diseases such as cancers, inflammatory diseases, and neurological disorders. HDAC complexes are composed of multiple subunits that assemble around HDAC enzymes, which have been the most exploited targets for developing small molecule therapeutics. To expand the diversity of targets and inhibitors available to study HDAC complex biology and fight HDAC-related diseases, the applicant developed phenotypic screens focused on the Sin3 HDAC complex in human and yeast during his PhD training. He also used proteomics approaches to study the global cellular effects of new compounds and predict their targets. However, the absence of high-resolution 3D structures for the Sin3 HDAC complex has hampered the precise understanding and validation of how drugs bind to specific subunits and perturb the overall architecture of the complex to reprogram its biological functions.Here, we are combining the expertise of the applicant in HDAC complex biology and druggability, to that of his host laboratory in cryo-electron microscopy (cryo-EM) to solve the 3D structures of the human and yeast Sin3 HDAC complex at near atomic resolution. This complex is highly conserved between species and is formed by a dozen proteins, making it an ideal candidate for single-particle cryo-EM. The applicant has already acquired promising preliminary data, including partial purifications of both human and yeast Sin3 HDAC complexes. The pioneer structures that will emerge from this work will have a high impact in the fields of transcriptomics and epigenetics since they will improve our understanding of HDAC complex arrangements, while helping validating long-standing hypotheses on transcriptional repression mechanisms. The proposed 3D models will also serve as starting points for further systematic structure-based design of new HDAC complex inhibitors.

Original text from CORDIS.

Participants

  • KATHOLIEKE UNIVERSITEIT LEUVEN · LeuvenCoordinatorBelgium

Links

Data: CORDIS, © European Union