Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates
Hannah K Long,
David Sims,
Andreas Heger,
Neil P Blackledge,
Claudia Kutter,
Megan L Wright,
Frank Grützner,
Duncan T Odom,
Roger Patient,
Chris P Ponting,
Robert J Klose
Affiliations
Hannah K Long
Department of Biochemistry, University of Oxford, Oxford, United Kingdom; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
David Sims
CGAT, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
Andreas Heger
CGAT, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
Neil P Blackledge
Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Claudia Kutter
Cancer Research UK – Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
Megan L Wright
School of Molecular and Biomedical Science, The Robinson Institute, University of Adelaide, Adelaide, Australia
Frank Grützner
School of Molecular and Biomedical Science, The Robinson Institute, University of Adelaide, Adelaide, Australia
Duncan T Odom
Cancer Research UK – Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Cambridge, United Kingdom
Roger Patient
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
Chris P Ponting
CGAT, MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
Robert J Klose
Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Two-thirds of gene promoters in mammals are associated with regions of non-methylated DNA, called CpG islands (CGIs), which counteract the repressive effects of DNA methylation on chromatin. In cold-blooded vertebrates, computational CGI predictions often reside away from gene promoters, suggesting a major divergence in gene promoter architecture across vertebrates. By experimentally identifying non-methylated DNA in the genomes of seven diverse vertebrates, we instead reveal that non-methylated islands (NMIs) of DNA are a central feature of vertebrate gene promoters. Furthermore, NMIs are present at orthologous genes across vast evolutionary distances, revealing a surprising level of conservation in this epigenetic feature. By profiling NMIs in different tissues and developmental stages we uncover a unifying set of features that are central to the function of NMIs in vertebrates. Together these findings demonstrate an ancient logic for NMI usage at gene promoters and reveal an unprecedented level of epigenetic conservation across vertebrate evolution.
