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Title: Understanding the assembly and function of the CoREST co-repressor complex
Author: Song, Yun
ISNI:       0000 0004 8498 4050
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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The CoREST complex was initially identified as a cofactor of the REST transcriptional repressor which plays important roles in regulating neuron-specific gene expression and neuronal stem cell fate. The CoREST complex contains several proteins including the histone deacetylases HDAC1 and HDAC2, the FADdependent demethylase LSD1 and the co-repressor protein CoREST. HDAC1, the first human HDAC identified, is only found in the nucleus and requires assembly into one of several co-repressor complexes for full activity. LSD1 is a FADdependent amine oxidase, which was identified as the first histone lysine demethylase and is associated with both transcriptional repression and activation. Whilst the structure of the complete LSD1/HDAC1/CoREST ternary complex is unknown, the structure of LSD1 has been solved bound to the interaction region from CoREST. In addition, previous studies in our group have reported the crystal structures of the HDAC3/SMRT and HDAC1/MTA1 co-repressor complexes and revealed that a SANT domain in both co-repressor proteins makes important interactions with the HDAC catalytic domain. Furthermore, an inositol phosphate molecule (IP) is sandwiched at the interface of the two proteins and regulates HDAC activity. I have successfully expressed and purified both the HDAC1/CoREST binary complex and the LSD1/HDAC1/CoREST ternary complex using a mammalian cell expression system. Both complexes are activated by inositol phosphates, and it has also shown that there is cross-talk between HDAC active site and inositol phosphates binding site. A new development enzymatic assay using 1D-NMR is applied to investigate the relationship between LSD1 and HDAC1 in the CoREST complex. Preliminary data highlight again the rigorous requirements of LSD1 substrate recognition. I have used SAXS approach combined with negative stain EM and chemical crosslinking/ mass spectrometry to build a structural model for the CoREST complex. This model provides the first image of the CoREST complex. Crystallization studies are still underway to determine the high resolution crystal structure of the complex.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Thesis