Málstofa Lífvísindaseturs: KRAB zinc finger protein essential for heart development

Málstofa Lífvísindaseturs föstudaginn 16. ágúst kl. 12:15 til 13:00 í Læknagarði, stofu 229.

Titill: A 320 million year old KRAB zinc finger protein cluster is essential for heart development and perinatal survival in mice

Fyrirlesari: Dr. Anna D. Senft, a visiting fellow at the NIH. Anna is a postdoctoral fellow in the research group led by Todd McFarlan at the NIH.

Here you can read an very inspiring interview with Anna by NICHD.

Ágrip:

Anna D Senft1, Peter Lindner1, Nick X Miller1, Shelley N Dolitzky1, Amanda N Ivanoff2, Alexander Grinberg1, Sherry A Ralls1, Todd S Macfarlan1 
1National Institutes of Health, The Eunice Kennedy Shriver National Institute for Child Health and Development, Bethesda, MD, 2University of Buffalo, Department of Biological Sciences, Buffalo, NY

Krüppel associated box (KRAB) zinc finger proteins (KZFPs) are the largest transcription factor family in humans and mice that evolved as an ‘immune system’ that targets endogenous retroviral sequences (ERVs) in vertebrates. Most KZFPs are species-specific and rapidly disappear as the ERVs they target become non-functional with little consequence for organism viability. Intriguingly, a subset of KZFPs have persisted in animal genomes suggesting they have been repurposed for host function. The vast majority of these conserved KZFPs remain unexplored. We identified an unusual cluster of conserved KZFPs that emerged 320 million years ago to be essential for perinatal survival in mice. The lethality is recapitulated by deleting a single member of the cluster, Zfp777. We identify a ventricular septal defect in hearts of Zfp777 KO embryos which could not only explain the lethality but also why the human ortholog ZNF777 is intolerant to mutations in healthy humans and is - when mutated - associated with a ventricular septal defect. Profiling of Zfp777 genome-wide occupancy in mouse embryonic stem cells identifies lack of localization to ERVs but binding to critical Polycomb-repressed developmental transcription factors, which Zfp777 represses during subsequent development. Lack of typical KZFP-associated repressive mechanisms and loss of Polycomb factors at a subset of target genes in Zfp777 KO mouse embryonic fibroblasts indicate that Zfp777 uses Polycomb-mediated repression to regulate gene expression. Intriguingly both KZFP- and Polycomb systems are capable of targeting ERVs. We propose that these two ancient repressive systems converged in the repurposing of the ancient KZFP cluster containing Zfp777 at the onset of amniote evolution to regulate developmental transcription factors crucial for organ development and postnatal survival.