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P 23 - Dr. Asifa Akhtar

Studying the molecular mechanisms underlying transcription regulation by the NSL complex



Dr. Asifa Akhtar

Max Planck Institute für Immunbiologie

Stübeweg 51

79108 Freiburg

Phone: +49 761 5108-565

Fax: +49 761 5108-566



Project Summary



My lab studies chromatin and epigenetic regulation mediated by MOF (Males absent On First) histone acetyltransferase associated complexes. Biochemical purifications led us to isolate a novel NSL complex (non-specific lethal) associated with MOF. Our genomewide analyses showed that the NSL complex is a chromatin bound complex that specifically targets promoters and acts as a major regulator of gene expression of house keeping genes. In the last funding period, we also generated an interaction map of binary interactions within the NSL complex. In particular, we identified new interactions for KANSL1, KANSL2 and WDR5 subunits in mammals and Drosophila respectively. High-resolution crystal structures of WDR5-KANSL1 and WDR5-KANSL2 sub-complexes have revealed that WDR5 uses the same residues for mutually exclusive interaction with KANSL1 and KANSL2 as it does for MLL and RbBP5 within the MLL/SET methyltransferase complex. By generating structure-based mutants in the Drosophila orthologues we showed that the KANSL1-WDR5 interaction is required for efficient recruitment of the NSL complex to target promoters and is essential for fly viability. Interestingly however, males and females show differences in the severity of the effect. We propose that WDR5 accommodates mutually exclusive interactions for integrating and separating signals within individual histone modifying complexes such as MOF histone acetyltransferase and MLL/Trx histone methyltransferase containing assemblies for distinct epigenetic regulation. During the next funding period, we plan to build on our findings and study the differential chromatin regulation of the NSL complex in males and females. Moreover, excitingly our recent preliminary analysis indicates that the NSL complex members may have additional roles outside of the nucleus. Hence, we plan to study the function of the NSL complex in mitochondrial homeostasis, which will provide novel insights into this dual role of this complex inside and outside of the nucleus.


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