title: Nuclear receptor HNF4α binding sequences are widespread in Alu repeats.
abstract: BACKGROUND
  Alu repeats, which account for ~10% of the human genome, were originally considered to be junk DNA. Recent studies, however, suggest that they may contain transcription factor binding sites and hence possibly play a role in regulating gene expression.
  
  
  RESULTS
  Here, we show that binding sites for a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors, hepatocyte nuclear factor 4alpha (HNF4α, NR2A1), are highly prevalent in Alu repeats. We employ high throughput protein binding microarrays (PBMs) to show that HNF4α binds > 66 unique sequences in Alu repeats that are present in ~1.2 million locations in the human genome. We use chromatin immunoprecipitation (ChIP) to demonstrate that HNF4α binds Alu elements in the promoters of target genes (ABCC3, APOA4, APOM, ATPIF1, CANX, FEMT1A, GSTM4, IL32, IP6K2, PRLR, PRODH2, SOCS2, TTR) and luciferase assays to show that at least some of those Alu elements can modulate HNF4α-mediated transactivation in vivo (APOM, PRODH2, TTR, APOA4). HNF4α-Alu elements are enriched in promoters of genes involved in RNA processing and a sizeable fraction are in regions of accessible chromatin. Comparative genomics analysis suggests that there may have been a gain in HNF4α binding sites in Alu elements during evolution and that non Alu repeats, such as Tiggers, also contain HNF4α sites.
  
  
  CONCLUSIONS
  Our findings suggest that HNF4α, in addition to regulating gene expression via high affinity binding sites, may also modulate transcription via low affinity sites in Alu repeats.
authors.affiliation: Department of Cell Biology and Neuroscience, University of California Riverside, Riverside, CA 92521, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bolotin
authors.forename: Karthikeyani
authors.initials: K
authors.lastname: Chellappa
authors.forename: Wendy
authors.initials: W
authors.lastname: Hwang-Verslues
authors.forename: Jake M
authors.initials: JM
authors.lastname: Schnabl
authors.forename: Chuhu
authors.initials: C
authors.lastname: Yang
authors.forename: Frances M
authors.initials: FM
authors.lastname: Sladek
mesh_terms: D020087:Alu Elements; D001665:Binding Sites; D019295:Computational Biology; D015894:Genome, Human; D057809:HEK293 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D011401:Promoter Regions, Genetic; D040081:Protein Array Analysis; D011485:Protein Binding / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D051557:Hepatocyte Nuclear Factor 4
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