Evidence of pioneer factor activity of an oncogenic fusion transcription factor

Benjamin D Sunkel; Meng Wang; Stephanie LaHaye; Benjamin J Kelly; James R Fitch; Frederic G Barr; Peter White; Benjamin Z Stanton

doi:10.1016/j.isci.2021.102867

Evidence of pioneer factor activity of an oncogenic fusion transcription factor

iScience. 2021 Jul 16;24(8):102867. doi: 10.1016/j.isci.2021.102867. eCollection 2021 Aug 20.

Authors

Benjamin D Sunkel¹, Meng Wang¹, Stephanie LaHaye², Benjamin J Kelly², James R Fitch², Frederic G Barr³, Peter White^{2

4}, Benjamin Z Stanton^{1

4

5}

Affiliations

¹ Nationwide Children's Hospital, Center for Childhood Cancer and Blood Diseases, Columbus, OH 43205, USA.
² The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.
³ Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
⁴ Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
⁵ Department of Biological Chemistry and Pharmacology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.

Abstract

Recent characterizations of pioneer transcription factors provide insights into their structures and patterns of chromatin recognition associated with their roles in cell fate commitment and transformation. Intersecting with these basic science concepts, identification of pioneer factors (PFs) fused together as driver translocations in childhood cancers raises questions of whether these fusions retain the fundamental ability to invade repressed chromatin, consistent with their monomeric PF constituents. This study defines the cellular and chromatin localization of PAX3-FOXO1, an oncogenic driver of childhood rhabdomyosarcoma (RMS), derived from a fusion of PFs. To quantitatively define its chromatin-targeting functions and capacity to drive epigenetic reprogramming, we developed a ChIP-seq workflow with per-cell normalization (pc-ChIP-seq). Our quantitative localization studies address structural variation in RMS genomes and reveal insights into inactive chromatin localization of PAX3-FOXO1. Taken together, our studies are consistent with pioneer function for a driver oncoprotein in RMS, with repressed chromatin binding and nucleosome-motif targeting.

Keywords: Molecular Genetics; Systems biology; Transcriptomics.