Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome

CHARGE syndrome is a rare genetic syndrome characterised by a unique combination of multiple organ anomalies. Dominant loss-of-function mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7), which is an ATP-dependent chromatin remodeller, have been identified as the cause of CHARGE syndrome. Here, we review recent work aimed at understanding the mechanism of CHD7 function in normal and pathological states, highlighting results from biochemical and in vivo studies. The emerging picture from this work suggests that the mechanisms by which CHD7 fine-tunes gene expression are context specific, consistent with the pleiotropic nature of CHARGE syndrome.
Trends The expressivity and penetrance of CHARGE phenotypes show little correlation with the CHD7 genotype. The hypothesis that mutations or polymorphisms in other genes modify disease phenotypes in humans remains unproven. CHARGE-associated CHD7 mutations can affect its nucleosome remodelling activity in vitro. The role of CHD7 in regulating nucleosome positioning in vivo and the effects of this activity on gene expression require further study. CHD7 pleiotropy may result from its interactions with cell type-specific transcription factors. CHD7 recruitment to cell type-specific enhancers may underlie context-specific roles.