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Open Access Research article

Nuclear Receptor HNF4α Binding Sequences are Widespread in Alu Repeats

Eugene Bolotin123, Karthikeyani Chellappa1, Wendy Hwang-Verslues14, Jake M Schnabl1, Chuhu Yang125 and Frances M Sladek12*

Author Affiliations

1 Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, CA, 92521, USA

2 Institute for Integrative Genome Biology, University of California, Riverside, Riverside, CA, 92521, USA

3 CHORI (Children's Hospital Oakland Research Institute), 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA

4 Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei 115, Taiwan

5 Roche Diagnostics Shanghai Limited, 1045 Central Huaihai Road, Shanghai 200031, China

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BMC Genomics 2011, 12:560  doi:10.1186/1471-2164-12-560

Published: 15 November 2011

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.