Understanding proteins that interpret genome context to stabilise cell states

The character of a cell is determined during differentiation by selective gene activation and silencing. In addition to high level decisions about which genes are on or off, it is now clear that levels of transcription in each differentiated cell must be precisely calibrated. This proposal seeks a comprehensive understanding of two proteins, SALL4 and MeCP2, that optimise transcription programmes in order to stabilise cellular states. Despite very different biological outputs, SALL4 and MeCP2 share striking similarities. Both are DNA binding proteins that recognise short, frequent DNA sequence motifs; both interact with histone deacetylase-containing corepressor complexes to modulate expression of many genes; and both are of proven biological and biomedical importance. Our intention is to study these proteins in parallel using a molecular genetic approach in order to elucidate fundamental mechanisms that consolidate cell identity before and after differentiation. To explore the generality of this form of transcriptional control, we will screen for novel transcription modulators that also interpret regionally variable genomic features by sensing short DNA sequence motifs. Our findings will have implications for regenerative medicine and reveal the molecular basis of diseases caused by deficiency of these and similar proteins, including Rett syndrome, Okihiro syndrome and cancer.