title: Deep sequencing reveals novel Set7 networks.
abstract: BACKGROUND
  Methyl-dependent regulation of transcription has expanded from a traditional focus on histones to encompass transcription factor modulation. While the Set7 lysine methyltransferase is associated with pro-inflammatory gene expression in vascular endothelial cells, genome-wide regulatory roles remain to be investigated. From initial characterization of Set7 as specific for methyl-lysine 4 of H3 histones (H3K4m1), biochemical activity toward non-histone substrates has revealed additional mechanisms of gene regulation.
  
  
  RESULTS
  mRNA-Seq revealed transcriptional deregulation of over 8,000 genes in an endothelial model of Set7 knockdown. Gene ontology identified up-regulated pathways involved in developmental processes and extracellular matrix remodeling, whereas pathways regulating the inflammatory response as well as nitric oxide signaling were down-regulated. Chromatin maps derived from ChIP-Seq profiling of H3K4m1 identified several hundred loci with loss of H3K4m1 at gene regulatory elements associated with an unexpectedly subtle effect on gene expression. Transcription factor network analysis implicated six previously described Set7 substrates in mRNA-Seq changes, and we predict that Set7 post-translationally regulates other transcription factors associated with vascular endothelial gene expression through the presence of Set7 amino acid methylation motifs.
  
  
  CONCLUSIONS
  We describe a role for Set7 in regulating developmental pathways and response to stimuli (inflammation/immune response) in human endothelial cells of vascular origin. Set7-dependent gene expression changes that occurred independent of H3K4m1 may involve transcription factor lysine methylation events. The method of mapping measured transcriptional changes to transcription factors to identify putative substrates with strong associations to functional changes is applicable to substrate prediction for other broad-substrate histone modifiers.
authors.affiliation: Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, VIC, 3004, Australia.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Keating
authors.forename: Mark
authors.initials: M
authors.lastname: Ziemann
authors.forename: Jun
authors.initials: J
authors.lastname: Okabe
authors.forename: Abdul Waheed
authors.initials: AW
authors.lastname: Khan
authors.forename: Aneta
authors.initials: A
authors.lastname: Balcerczyk
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D059014:High-Throughput Nucleotide Sequencing; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008745:Methylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D034741:RNA, Small Interfering; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human