Poster Presentation 47th Lorne Genome Conference 2026

Embryonic stem cell factors DPPA2/4 facilitate poised chromatin states in non-small cell lung cancer (133029)

Janith Seneviratne 1 2 , Clare Crisp 2 , Eleanor Glancy 1 2 , Natalie Choy 2 , Winnie Tan 3 , Matt Neve 1 2 , Melanie Stammers 4 , Tongtong Wang 2 , Ruby Johnstone 2 , Arshnoor Kaur 2 , Katie Fennell 2 , Marian Burr 5 , Benjamin Parker 6 , Shabih Shakeel 3 , Melanie Eckersley-Maslin 1 2 6
  1. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Australia
  3. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  4. Babraham Institute, Cambridge, United Kingdom
  5. The John Curtin School of Medical Research, The Australian National University, ACT, Australia
  6. Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Australia

Embryonic genes that regulate normal development are often re-expressed in cancers, yet the functional and molecular consequences of this phenomenon are poorly understood. The epigenetic priming factors Developmental Pluripotency Associated 2 and 4 (DPPA2&4) play crucial roles in early development and are implicated in cancer pathogenesis. We revealed co-expression of DPPA2&4 is associated with poorly differentiated tumours and impaired patient survival in non-small cell lung cancer (NSCLC) subtypes. Consistently, overexpression of DPPA2&4 in human NSCLC cells demonstrated accelerated in vivo xenograft tumour growth. Through proteomic analyses (IP/RIME-MS, EMSA), we found that DPPA2&4 heterodimerise to enhance their protein stability and binding efficiency to nucleosomes. Through multi-omic epigenome profiling (ChIP, CUT&Run, ATAC-seq, BS-seq) and transcriptome analyses (RNA-seq) we found DPPA2&4 associated with and promote active chromatin states in NSCLC. Depleting DPPA2&4 in these NSCLC cells, uncovered a function for DPPA2&4 in maintaining the PRC1 complex (RING1B) and it’s product H2AK119ub at active promoters and enhancers. Surprisingly, these DPPA2&4 regulated H2AK119ub domains lacked detectable repressive H3K27me3 (deposited by the PRC2 complex), despite the presence of the PRC2 complex at some of these sites. Ablation of H3K27ac (deposited by p300/CBP) at these regions using the p300/CBP inhibitor A-485 revealed that DPPA2&4 regulated genes were primed for repression upon H3K27ac removal, elucidating a novel gene poising mechanism. Our results support a model by which DPPA2&4 act as amplifiers of active chromatin states, facilitating the binding and/or activity of chromatin regulators at these domains and ultimately facilitating the detrimental outcomes seen in patients with DPPA2&4 expressing cancers. Our study reveals how aberrant expression of embryonic chromatin regulators in cancers can facilitate alternate chromatin states to regulate gene expression in aggressive tumours.