Professor Tom Strachan
Professor of Human Molecular Genetics

  • Email: tom.strachan@ncl.ac.uk
  • Telephone: +44 (0) 191 241 8616
  • Fax: +44 (0) 191 241 8666
  • Address: Institute of Human Genetics
    International Centre for Life
    Central Parkway
    Newcastle upon Tyne
    NE1 3BZ

Research Interests

The function of the vertebrate Nipbl-Mau2 complex

Developmental gene regulation

My research is focused on developmental gene regulation. We recently identified a previously unstudied gene, NIPBL, as the major locus of a developmental malformation, Cornelia de Lange syndrome. The NIPBL protein, also called delangin, has been very highly conserved during evolution and it has counterparts in fungi, plants, worms, flies, and vertebrates. Previous studies of the fly homologue, Nipped-B, indicate that it regulates the Ultrabithorax and cut homeobox genes and interacts with components of Notch signalling pathways. It appears to work by facilitating long-range enhancer-promoter interactions in its target genes, most likely by modifying chromatin structure. Yeast orthologues, such as Scc2 and Mis4, are known to regulate sister chromatid cohesion and pairing of homologous chromosomes by regulating loading of cohesins not chromatin, and they are also involved in double strand DNA repair.

More recently we showed that the NIPBL protein interacts with a previously unstudied human protein, KIAA0892, and that this complex loads cohesin complexes onto human chromatin. KIAA0892 is the human orthologue of both the budding yeast Scc4 sister chromatid cohesion protein and also C. elegans MAU-2, a factor that is known to guide the migration of cells and axons during development. More recently, by using RNA interference to knock down Nipbl or Mau2 in zebrafish embryos we have shown that both of these genes regulate axon migration too.

Developmental gene regulation

The current data indicate that an evolutionarily ancient complex that serves to regulate loading of cohesins onto chromatin (Scc2-Scc4 in budding yeast) has been conserved in metazoans but has acquired additional roles in developmental gene regulation. Mammalian cohesin complexes are now known to be recruited to a subset of DNase I hypersensitive sites and to conserved noncoding sequences by the DNA-binding protein CTCF. The CTCF protein functions at insulators (which control interactions between enhancers and promoters) and at boundary elements (which demarcate regions of distinct chromatin structure), and cohesins contribute to enhancer-blocking activity.

To further investigate the functions of vertebrate Nipbl and Mau2 we have recently used gene targeting to make conditional knockouts of both Nipbl and Mau2 in mice, in collaboration with Dr. Heiko Peters. We are currently analyzing the phenotypes of the different knockout mouse strains.