The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure

MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.

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Policy information about availability of computer code Data collection John Schwabe May 27, 2020 EM data was collected on a ThermoFisherTitan Krios using EPU 1.9 RNAseq data was collected by Novogene using an Illumina PE150, Q30; 20 million reads Flow cytometry samples were analysed using a BD AccuriTM C6 flow cytometer (BD Biosciences).

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October 2018

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All studies must disclose on these points even when the disclosure is negative. The EM maps for the dimer and tetramer are available from EMDB (EMD-11041 and EMD-11042). The coordinates for the dimer and tetramer models are available from the PDB (6Z2J and 6Z2K). The RNAseq data that support the findings of this study have been deposited in GEO with the primary accession code GSE144748. The source data underlying Figures 1, 2, and 3 and Supplementary Figures 1, 3, 4, 5, 6, 9 and 12 are provided as a Source Data file.
For mouse MEF embryo analysis at least 2 wildtype or homozygous embryos were used to account for technical and biological variation. For RNAseq using MEF samples at least 20000000 read pairs were generated per sample. For in vitro experiments at least 3 independent experiments were conducted to account for biological and technical variability. No statistical methods were used to determine size. Statistical tests were then performed using GraphPad to provide confidence in the conclusions made.
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