title: PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse.
abstract: BACKGROUND
  Genome-wide comparisons of transcription factor binding sites in different species can be used to evaluate evolutionary constraints that shape gene regulatory circuits and to understand how the interaction between transcription factors shapes their binding landscapes over evolution.
  
  
  RESULTS
  We have compared the PPARG binding landscapes in macrophages to investigate the evolutionary impact on PPARG binding diversity in mouse and humans for this important nuclear receptor. Of note, only 5% of the PPARG binding sites were shared between the two species. In contrast, at the gene level, PPARG target genes conserved between both species constitute more than 30% of the target genes regulated by PPARG ligand in human macrophages. Moreover, the majority of all PPARG binding sites (55-60%) in macrophages show co-occupancy of the lineage-specification factor PU.1 in both species. Exploring the evolutionary dynamics of PPARG binding sites, we observed that PU.1 co-binding to PPARG sites appears to be important for possible PPARG ancestral functions such as lipid metabolism. Thus we speculate that PU.1 may have guided utilization of these species-specific PPARG conserved binding sites in macrophages during evolution.
  
  
  CONCLUSIONS
  We propose a model in which PU.1 sites may have served as "anchor" loci for the formation of new and functionally relevant PPARG binding sites throughout evolution. As PU.1 is an essential factor in macrophage biology, such an evolutionary mechanism would allow for the establishment of relevant PPARG regulatory modules in a PU.1-dependent manner and yet permit for nuanced regulatory changes in individual species.
authors.affiliation: Cancer Biology and Pharmacology 2, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pott
authors.forename: Nima K
authors.initials: NK
authors.lastname: Kamrani
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D016384:Consensus Sequence; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs; D047495:PPAR gamma / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D047488:Retinoid X Receptors / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D024363:Transcription Initiation Site; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D047495:PPAR gamma; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D047488:Retinoid X Receptors; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1