Poster Presentation 16th Asian Conference on Transcription 2019

The role of ZBTB7A in foetal globin repression (1172)

Lana Ly 1 , Kate G.R Quinlan 1 , Merlin Crossley 1
  1. University of New South Wales, Kensington, NSW, Australia

The globin loci encode subunits of haemoglobin, an oxygen-carrying protein that is abundant in red blood cells. Beta-haemoglobinopathies, such as sickle cell anaemia and beta-thalassemia, arise from mutations in the adult beta-globin gene. There are no fully effective treatments for these conditions and since the number of affected infants born each year is rising as populations increase across areas with high carrier rates, the search for effective long-term treatments is ongoing.

Reactivation of the silenced foetal gamma-globin genes can compensate for dysfunctional adult beta-globin and alleviates symptoms. One strategy towards reactivating the foetal globin genes is to interfere with the mechanism of repression. We have shown that the Zinc Finger and BTB Domain Containing 7A (ZBTB7A) acts by binding to the -200 proximal promoter site and directly represses foetal globin expression.

Here we investigate ZBTB7A’s mechanism of action. ZBTB7A consists of four classical zinc fingers and an N-terminal POZ domain that can mediate self-association and contact to partner proteins. We have investigated the sequence recognition motifs of individual zinc fingers and the requirement for self-association via the POZ domain. We are investigating a model whereby ZBTB7A may bind at multiple sites across the locus to ensure the appropriate 3D topology of the locus, including looping of the power Locus Control Region enhancer to individual globin gene promoters.