Structural Maintenance of Chromosomes, Hinge Domain containing 1 (Smchd1) is an epigenetic modifier involved in transcriptional repression that is critical for the maintenance of X Chromosome Inactivation. Smchd1 also regulates gene expression at a number of autosomal loci, however we don’t understand the molecular mechanisms by which it is involved in transcriptional repression.

Recently both gain and loss of function mutations in SMCHD1 have been found to underlie Bosma arhinia micropthalmia syndrome (BAMS) and Facioscapulohumoral muscular dystrophy 2 (FSHD2), respectively - two distinct developmental disorders. While loss of SMCHD1 function has been well characterised in both mouse and human, currently little is known about the molecular consequences for gain of SMCHD1 function.

There is evidence to suggest that Smchd1 may be involved in regulating higher order chromatin structure (Chen et al. PNAS 2015, Nozawa et al. Nat Struct Mol Biol 2013). In order to determine how altered Smchd1 function affects the chromatin architecture, we have performed in-situ Hi-C and ATAC-seq in Smchd1 wild-type and deleted neural stem cells, and cells that harbor a gain of function mutation in Smchd1. This data is being integrated with ChIP-seq and RNA-seq data, to understand how loss and gain of Smchd1 function affects chromatin structure and gene expression. We further aim to determine whether changes to the chromatin architecture are a direct or indirect consequence of altered Smchd1 function, using a range functional and biochemical techniques.

Previously we have shown that the hinge domain of Smchd1 binds synthetic DNA and RNA oligonucleotides with micromolar affinity (Chen et al. PNAS 2015). We are interested in how Smchd1 interacts with endogenous nucleic acids and whether these interactions are important in regulating transcription or targeting Smchd1 to chromatin. To this end we have performed PAR-CLIP to determine whether Smchd1 binds endogenous RNAs genome wide, and are investigating how the hinge domain of Smchd1 interacts with nucleic acids, and whether it has a role in targeting Smchd1 to the inactive X chromosome.