title: Changes in the enhancer landscape during early placental development uncover a trophoblast invasion gene-enhancer network.
abstract: BACKGROUND
  Trophoblast invasion establishes adequate blood flow between mother and fetus in early placental development. However, little is known about the cis-regulatory mechanisms underlying this important process. We aimed to identify enhancer elements that are active during trophoblast invasion, and build a trophoblast invasion gene-enhancer network.
  
  
  METHODS
  We carried out ChIP-Seq for an enhancer-associated mark (H3k27Ac) at two time points during early placental development in mouse. One time point when invasion is at its peak (e7.5) and another time point shortly afterwards (e9.5). We use computational analysis to identify putative enhancers, as well as the transcription factor binding sites within them, that are specific to the time point of trophoblast invasion.
  
  
  RESULTS
  We compared read profiles at e7.5 and e9.5 to identify 1,977 e7.5-specific enhancers. Within a subset of e7.5-specific enhancers, we discovered a cell migration associated regulatory code, consisting of three transcription factor motifs: AP1, Ets, and Tcfap2. To validate differential expression of the transcription factors that bind these motifs, we performed RNA-Seq in the same context. Finally, we integrated these data with publicly available protein-protein interaction data and constructed a trophoblast invasion gene-enhancer network.
  
  
  CONCLUSIONS
  The data we generated and analysis we carried out improves our understanding of the regulatory mechanisms of trophoblast invasion, by suggesting a transcriptional code exists in the enhancers of cell migration genes. Furthermore, the network we constructed highlights novel candidate genes that may be critical for trophoblast invasion.
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Geetu
authors.initials: G
authors.lastname: Tuteja
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Tisha
authors.initials: T
authors.lastname: Chung
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA. Electronic address: bejerano@stanford.edu.
authors.forename: Gill
authors.initials: G
authors.lastname: Bejerano
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D062126:Databases, Chemical; D004622:Embryo, Mammalian; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D005260:Female; D053263:Gene Regulatory Networks; D051379:Mice; D010929:Placentation / Q000235:genetics*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D060066:Protein Interaction Maps; D014157:Transcription Factors / Q000378:metabolism; D014327:Trophoblasts / Q000502:physiology*
chemical_list: D014157:Transcription Factors
keywords: Cis-regulation; Gene-enhancer network; Trophoblast invasion