Research
Recently we have been focussing on naturally occurring mutations that boost fetal globin gene expression, and are associated with Hereditary Persistence of Fetal Hemoglobin (HPFH). We have characterised the mechanisms of action of point mutations in the fetal globin promoter, and larger deletions that remove the adult promoter and alleviate enhancer competition. Editing in these mutations with CRISPR represents the latest therapy for beta-hemoglobinopathies, such as Sickle Cell Disease and thalassemia.
Understanding how methylation affects fetal globin gene expression
Understanding how transcription factors identify their target genes, via domains other than the DNA-binding domain
The genomic localisation of transcription factors (TFs) was traditionally thought to be solely determined by their DNA binding domains (DBDs) binding to a specific DNA motif. However, in vivo studies such as early ChIP-seq experiments demonstrated that TFs only bind a fraction of their motifs (often <1%) in vivo. This led us and others to investigate other factors that affect specificity. Using a model zinc finger TF, KLF3, we have previously shown that its functional or effector domain via protein-protein interactions also influences its genomic localisation. We are now further exploring how this translates to the whole KLF family and how epigenetic partner proteins may be involved.
Exploring and manipulating the nucleosomal landscape to influence gene regulation