Oral Presentation 40th Annual Lorne Genome Conference 2019

FOXK proteins are evolutionarily conserved DNA methylation readers required for vertebrate embryogenesis  (#41)

Michael Geng 1 , Alex de Mendoza 2 , Arne Smits 3 , Irem Baymaz 3 , Eliza de la Calle Mustienes 4 , Michiel Vermelen 3 , Jose Luis Gomez-Skarmeta 4 , Ryan Lister 5 , Ozren Bogdanovic 1 6
  1. Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Australian Research Council Centre of Excellence in Plant Energy Biology, University of Western Australia, Perth, WA, Australia
  3. Department of Molecular Biology Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, Netherlands
  4. Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Seville, Spain
  5. Australian Research Council Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, WA, Australia
  6. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

DNA methylation (5mC) is a gene-regulatory mark mostly associated with transcriptional repression. Research carried out over the last decade has, however, revealed that the amount of 5mC in gene regulatory regions does not always correlate with transcriptional repression. Indeed, a wealth of recent studies have conclusively demonstrated that the interactions between 5mC and transcription factors are highly complex and are far from being understood. Indeed, many transcription factors are not repelled but rather attracted by 5mC, which could potentially serve as an additional mechanism for achieving target-site specificity. Here we set out to explore the 5mC-binding properties of the multifaceted transcriptional regulators FOXK1/2. We reveal that FOXK proteins bind methylated DNA in both anamniotes and mammals and that the FOXK forkhead domain governs this binding. Furthermore, through loss of function assays in zebrafish we demonstrate the embryonic requirements for FOXK1/2 proteins during embryogenesis. RNA-seq profiling of FOXK morphants revealed robust transcriptional misregulation linked to genes associated with cell cycle control, as previously shown in mammals. Overall, our study describes a novel family of 5mC readers and further elaborates on their functions during development and differentiation.