From: Wellcome Trust Centre for Cell Biology, University of Edinburgh

Will give a seminar entitled:

SALL4 Controls Cell Fate in Response to DNA Base Composition

Mammalian genomes are divided into large domains characterised by distinct compositions of A/T versus G/C nucleotides. While these genomic features are evolutionarily conserved, their functional relevance remains unknown. We hypothesised that a certain class of proteins could “read” DNA base composition to regulate gene expression and cell fate. We identified SALL4 as a top hit in a screen for AT-binding proteins in mouse embryonic stem cells. SALL4 contains a specific zinc-finger cluster responsible for binding to short AT-rich DNA motifs (ZFC4). Strikingly, SALL4 ZFC4 is responsible for the repression of differentiation-associated genes in proportion to the AT-content across the body of these genes. ZFC4 mutation mimics defects seen in Sall4 knockout, including abnormal neuronal differentiation and early embryonic lethality. Accordingly, missense mutations within ZFC4 cause Okihiro syndrome, a developmental disorder caused by SALL4 haploinsufficiency. Our current efforts aim at validating our working model, in which SALL4 represses the expression of AT-rich genes by recruiting the NuRD co-repressor complex. 

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