Towards a structural understanding of transcriptional regulation by ZMYM2-KDM1A-CoREST

PROJECT SUMMARY / ABSTRACT Tight regulation of transcription is critical for human health. ZMYM2 associates with the KDM1A-CoREST complex on chromatin and acts as a localization signal for complex partners mediating transcriptional repression. Detailed understanding of how transcription factors, like ZMYM2, recruit chromatin modifying complexes to specific promoters and achieve transcriptional regulation is lacking. Several pediatric cancers emerge due to disruption in chromatin and epigenetic states. Gene regulation has long been considered "undruggable". Mechanistic studies of transcriptional regulation will build the foundation for the development of new therapeutic approaches to modulate chromatin and gene regulatory machineries. KDMA1 is a promising target for epigenetic regulation, several KDM1A inhibitors are under development for acute myeloid leukemia, but further investigation is required to enhance our understanding of the underlying mechanism of therapeutics modifying gene expression on a molecular level. As a postdoc in the Fischer and Armstrong laboratory, I aim to strengthen my ability to innovate and advance experimental therapeutics in the field of pediatric hematologic malignancies and more importantly supplement my previous skillset in cancer biology with integrative structural biology and mechanism-based research. I am developing expertise in biochemical and structural biology so that I can help drive the understanding of aberrant transcription in pediatric cancer and lay the groundwork for new therapeutic development. I propose a multifaceted approach combining proteomics, biochemical characterization, functional assays, and cryo-electron microscopy studies of the ZMYM2-KDM1A-CoREST complex to understand the regulation of gene expression by ZMYM2-KDM1A-CoREST and more generally how transcription is regulated on a molecular level. I propose to determine a high-resolution three-dimensional structure of the ZMYM2-KDM1A-CoREST complex, providing insights into the molecular mechanisms by which transcriptional regulation is achieved (aim 1). I will then characterize the function of transcription factors and members of distinct chromatin modifying complexes in vitro. I will study how transcription factors, like ZMYM2 directly mediate the demethylation or deacetylation of histones by its interacting proteins KDM1A or HDACs, respectively (aim 2). Finally, I will characterize the role of ZMYM2-KDM1A-CoREST at specific promotors in various biological settings in the living cell (aim 3). Understanding how ZMYM2-KDM1A-CoREST mediates transcriptional regulation can inform general approaches to modulate aberrant transcription. Overall, this study aims to provide a deep understanding of the molecular mechanisms underlying transcriptional regulation in a cell type and fate specific manner. The results of this study will inform the development of new therapeutics targeting aberrant transcription in pediatric hard-to- treat cancers.