Poster Presentation 44th Lorne Genome Conference 2023

Survey of activation-induced genome architecture reveals a novel enhancer of Myc (#258)

Wing Fuk Chan 1 2 , Hannah Coughlan 1 2 , Michelle Ruhle 1 2 , Nadia Iannerella 1 2 , Carolina Alvarado 1 2 , Joanna Groom 1 2 , Christine Keenan 1 2 , Andrew Kueh 1 2 , Adam Wheatley 3 , Gordon Smyth 1 4 , Rhys Allan 1 2 , Timothy Johanson 1 2
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Dept. of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  3. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, , Melbourne, Victoria, Australia
  4. Department of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia

The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture (in situ HiC) to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of Myc. The interactivity of this enhancer coincides with a dramatic, but extremely discrete, spike in Myc expression 3 hours post-activation. However, genetic deletion of this region in mice, has little impact on Myc expression, Myc protein level or in vitro and in vivo immune cell proliferation. Closer examination of the enhancer deleted three-dimensional regulatory landscape reveals increased interactivity between the Myc promoter and enhancers downstream of the deletion, suggesting that enhancer redundancy likely sustains Myc expression in the absence of the activation-induced enhancer. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc.