Structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1) is a non-canonical SMC family protein, which contains an ATPase domain, an SMC hinge domain, and an uncharacterized central region. SMCHD1 is an epigenetic repressor and plays critical roles on both the inactive X chromosome and autosomes. Perturbing SMCHD1 can disrupt the repression of its targets, but the mechanisms by which it elicits epigenetic and transcriptional silencing remains unknown. SMCHD1 is also implicated in human diseases Facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS). In both disorders, variants in SMCHD1 were reported and are relevant to the onset of the disease. How these variants impair SMCHD1’s function and further lead to disease is still mysterious.
In my PhD, I will try to unravel the mechanism of SMCHD1 by combining point mutant SMCHD1-GFP mice with advanced live cell imaging and genomics. First, I will develop inducible mouse lines which contain mutations that activate or inhibit SMCHD1’s ATPase activity or deplete nucleic acid interaction of the hinge domain. I will analyze SMCHD1-GFP dynamics at the chromatin via FRAP, FLIM-FRET, and lattice light sheet microscopy. Such experiments will tell us how SMCHD1’s ATPase activity and nucleic acid interaction contribute to SMCHD1’s dynamic behavior. I will use genomic assays to decipher the influence of mutant SMCHD1 at a genomic level, meaning together I can learn about SMCHD1’s exact mechanism of action. Since several of the point mutations I will study are pathogenic variants found in disease, my project will provide a deep understanding of how SMCHD1 function is altered in these cases and may reveal potential strategies to target SMCHD1 to treat these diseases.