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Towards a structural and functional understanding of the MIER1 co-repressor complex
thesisposted on 18.03.2021, 14:38 by Siyu Wang
Histone deacetylase enzymes (HDACs) are interesting as potential cancer drug targets because they are able to regulate the expression of genes by removing acetyl groups from lysine residues in histone tails, and are therefore linked to gene silencing. Altered gene expression and the formation of mutations encoding HDACs have been connected to the development of tumours as they both cause abnormal transcription of genes which control important cell functions like cell proliferation, cell-cycle regulation and cell death (apoptosis). Therefore, HDAC inhibitors are a fertile ground for investigation and research in the quest for more effective epigenetic anti-cancer drugs. MIER1 (mesoderm induction early response) which was previously known as er1 was first isolated as a fibroblast growth factor regulated gene in Xenopus lavis. The MIER family contains MIER1, 2 and 3. The function of MIER1 depends on its localization in the nucleus, however it contains no functioning NLS and so it relies on interaction and co-transport with HDAC1 and 2 for translocation to the nucleus. The MIER1 complex is one of the class I HDAC co-repressor complexes containing HDAC1 and part of BAHD1
(Bromo adjacent homology domain containing protein 1). MIER1 regulates gene expression in fibroblast growth. However, the mechanism of how MIER1 recruits HDAC1 and BAHD1 has not been well characterised. The MIER1/HDAC1 complex has been successfully expressed using HEK293F suspension cells. The complex has been found to co-purify the endogenous H2A and H2B. Mapping experiments and NMR have demonstrated that MIER1 recruits H2A and H2B through its N-terminal region. It has also been determined that the BAH domain of BAHD1 can form a complex with MIER1/HDAC1. The structure of the MIER1 complex has been studied using negative stain electron microscopy and X-ray crystallography.