title: Effects of gene regulatory reprogramming on gene expression in human and mouse developing hearts.
abstract: Lineage-specific regulatory elements underlie adaptation of species and play a role in disease susceptibility. We compared functionally conserved and lineage-specific enhancers by cross-mapping 5042 human and 6564 mouse heart enhancers. Of these, 79 per cent are lineage-specific, lacking a functional orthologue. Heart enhancers tend to cluster and, commonly, there are multiple heart enhancers in a heart locus providing a regulatory stability to the locus. We observed little cross-clustering, however, between lineage-specific and functionally conserved heart enhancers suggesting regulatory function acquisition and development in loci previously lacking heart activity. We also identified 862 human-specific heart enhancers: 417 featuring sequence conservation with mouse (class II) and 445 with neither sequence nor function conservation (class III). Ninety-eight per cent of class III enhancers were deleted from the mouse genome, and we estimated a similar-sized enhancer gain in the human lineage. Human-specific enhancers display no detectable decrease in the negative selection pressure and are strongly associated with genes partaking in the heart regulatory programmes. The loss of a heart enhancer could be compensated by activity of a redundant heart enhancer; however, we observed redundancy in only 15 per cent of class II and III enhancer loci indicating a large-scale reprogramming of the heart regulatory programme in mammals.
authors: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health (NIH), Bethesda, MD 20892 USA.
authors: Chih-Hao
authors: CH
authors: Hsu
authors: Ivan
authors: I
authors: Ovcharenko
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D002874:Chromosome Mapping; D017124:Conserved Sequence; D018899:CpG Islands; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D015894:Genome, Human; D006321:Heart / Q000196:embryology / Q000254:growth & development*; D006801:Humans; D051379:Mice; D012641:Selection, Genetic; D059467:Transcriptome
keywords: cis-regulatory evolution; gene regulation; lineage-specific heart enhancers
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