Oral Presentation ASSCR, AGCTS, ISCT ANZ and Friends Joint Scientific Conference 2019

Conserved Epigenetic Regulatory Logic Infers Genes Governing Cell Identity (#4)

Enakshi Sinniah 1 , Woo Jun Shim 2 , Jun Xu 1 , Burcu Vitrinel 3 , Michael Alexenian 4 , Gaia Andreoletti 5 , Sophie Shen 1 , Brad Balderson 2 , Guangdun Peng 6 , Naihe Jing 7 , Yuliangzi Sun 1 , Yash Chhabra 8 , Yuliang Wang 9 , Patrick PL Tam 10 , Aaron Smith 11 , Michael Piper 11 , Lionel Christaen 3 , Quan Nguyen 1 , Mikael Boden 2 , Nathan J Palpant 1
  1. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
  2. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
  3. Center For Developmental Genetics, New York University, New York, United States
  4. The Gladstone Institute, University Of California San Francisco, San Francisco, United States
  5. Institute For Computational Health Sciences, University Of California, San Francisco, United States
  6. Cas Key Laboratory Of Regenerative Biology, University Of Chinese Academy Of Sciences, Guangzhou, China
  7. State Key Laboratory Of Cell Biology, University Of Chinese Academy Of Sciences, Shanghai, China
  8. Institute Of Health And Biomedical Innovation, Queensland University Of Technology, Brisbane, Australia
  9. Department Of Computer Science, University Of Washington, Seattle, United States
  10. Children's Medical Research Institute, The University Of Sydney, Westmead, Australia
  11. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia

Understanding genetic control of cell diversification is essential for establishing mechanisms controlling biological complexity. We analyzed 111 NIH epigenome roadmap data sets to identify distinguishing features of genome regulation associated with cell-type specification. We show that the a priori deposition of H3K27me3, which we call a gene’s repressive tendency (RT), provides a genome-wide enrichment for genes governing fundamental mechanisms underlying biological complexity in cell differentiation, organ morphogenesis and drivers of disease. We tested the ability to infer regulatory genes controlling theoretically any somatic cell by interfacing genome-wide RT values with cell-specific genome-wide sequencing data. Using more than 1 million genome-wide data sets from diverse omics platforms including bulk and single cell RNA-seq, CAGE-seq, ChIP-seq and quantitative proteomics, we identify cell-type specific regulatory mechanisms underlying diverse cell-states, organ systems and disease pathologies. Since regulatory control of cell identity is highly evolutionarily conserved across species, we demonstrate that this computational logic enriches for cell- type specific regulatory genes from species across the animal kingdom including chordates and arthropods. Lastly, we use this computational inference approach for novel gene discovery. Analysis of single cell RNA-seq data from in vitro human iPSC cardiac differentiation predicted SIX3 as a novel transcription factor controlling derivation of definitive endoderm, which we confirmed by SIX3 genetic loss of function using CRISPRi hPSCs. Moreover, analysis of transcriptional data from heart development of the invertebrate chordate Ciona robusta, predicted RNF220 to underlie tunicate heart field formation. This was confirmed with CRISPR knockout in vivo showing that RNF220 loss of function results in pharyngeal muscle morphogenesis defects. This study demonstrates that the conservation of epigenetic regulatory logic provides an effective strategy for utilizing large, diverse genome-wide data to establish quantitative basic principles of cell-states to infer cell-type specific mechanisms that underpin the complexity of biological systems.

  • Have you presented your abstract at another international meeting?: No