Chromatin remodeling—the dynamic structural changes in proteins that regulate access to DNA for the control of replication, gene expression, and DNA repair—plays an important role in the function of the cell, and its dysregulation can lead to cancer. More than 20% of human cancers involve mutations in genes that encode components of the multi-subunit protein complexes that regulate chromatin remodeling. Inactivating mutations in chromatin remodeling genes can result in a loss of expression of downstream tumor suppressor genes. When the SWI/SNF complex is inactivated, for example, it fails to activate transcription of the STAT1 gene, which encodes a component of interferon signaling important for tumor suppression. Molecular biologist H. Courtney Hodges at Baylor College of Medicine and molecular pharmacologist Nathaniel Hathaway at the University of North Carolina Chapel Hill are exploring a novel approach to artificially compensate for dysfunctional SWI/SNF complexes. They will use bifunctional small molecules to bring into close proximity proteins that can activate SWI/SNF-dependent transcriptional enhancers in the absence of SWI/SNF. The STAT1 gene locus will serve as the test case for this strategy. This study will demonstrate whether induced proximity by small molecules can be utilized to modulate epigenetic regulation and will lay the groundwork for future development of first-in-class molecules capable of restoring tumor-suppressive transcription factor networks in SWI/SNF-deficient cancers.
Cermakova K, Demeulemeester J, Lux V, Nedomova M, Goldman SR, Smith EA, Srb P, Hexnerova R, Fabry M, Madlikova M, Horejsi M, De Rijck J, Debyser Z, Adelman K, Hodges HC, Veverka V. A ubiquitous disordered protein interaction module orchestrates transcription elongation. Science. 2021.
Lu D, Foley CA, Birla SV, Hepperla AJ, Simon JM, James LI, Hathaway NA. Bioorthogonal Chemical Epigenetic Modifiers Enable Dose-Dependent CRISPR Targeted Gene Activation in Mammalian Cells. ACS Synth Biol. 2022.