Monday, June 2, 2025
6/2/2025
Epigenetic regulation of transcriptional programming - ABSTRACT Cell type-specific transcriptional programming enables a single fertilized egg to make the remarkable transition to become a multicellular organism. The requisite sequence of gene expression transitions is the result of a collaboration between cell type-specific transcription factors and broadly expressed chromatin regulators. Historically, my group has made significant contributions to understanding the targeting and spreading of chromatin domains, and currently we are probing the ability of modular chromatin factors to respond to local concentrations of transcription factors and their co-activators to specify cell type. Our studies focus on the dynamic competition between Polycomb (PcG) and Trithorax group (TrxG) proteins, and due to the high conservation of these key regulatory factors we move between fly embryos and mammalian cells with ease. We have recently contributed to the recognition of the ancient conservation of alternative forms of PcG complexes, and over the next funding period we will investigate the distinct molecular roles that must underly this remarkable conservation. To understand when, where, and how variant Polycomb complexes function, the Drosophila melanogaster embryonic and germline systems harbor special promise for key aspects of this work. In particular, emerging approaches in the germline will allow us to dissect the earliest events in the establishment of PcG/TrxG regulation. A key challenge will be to adapt current methods to integrate alternative configurations of protein complexes with their local binding patterns and genetic knockdown phenotypes. For example, we have discovered that a Pho/Sfmbt protein module can interact with co- activators as well as variant PRC1.6 complexes in Drosophila embryos, and we will test whether these are modular interactions that vary on a gene-by-gene basis during normal development. We will also analyze aberrant epigenetic programs in mammalian cells, in light of the important role that a dynamic PcG/TrxG competition plays in human malignancies. Focusing on chromatin-driven cancers caused by aberrant TrxG fusion oncoproteins such as MOZ-TIF2 will complement our analyses of normal cell type transitions. This topic is of key biomedical significance, as plasticity of transcriptional programming is thought to underlie the devastating facility of cancer sub-populations to acquire drug resistance and to metastasize. Important benchmarks for our work will be i) identifying the initial steps that poise developmental genes for activation or repression, ii) providing a mechanistic understanding for how resolution occurs, and iii) contributing to an understanding of cell state switching in response to cancer drivers. More broadly, our work will highlight regulation at the level of dynamic protein interactions, which is likely universal to all biological systems.
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