Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 7, Pages 4230-4240Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt1401
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Funding
- Academy of Finland
- Sigrid Juselius Foundation
- Finnish Cancer Foundations
- Biocentrum Helsinki
- Helsinki University Central Hospital
- Helsinki Biomedical Graduate Program
- KU Leuven [OT/11/081]
- Fund for Scientific Research Flanders (FWO)
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The DNA-binding domains (DBDs) of class I steroid receptors-androgen, glucocorticoid, progesterone and mineralocorticoid receptors-recognize a similar cis-element, an inverted repeat of 5'-AGAACA-3' with a 3-nt spacer. However, these receptors regulate transcription programs that are largely receptor-specific. To address the role of the DBD in and of itself in ensuring specificity of androgen receptor (AR) binding to chromatin in vivo, we used SPARKI knock-in mice whose AR DBD has the second zinc finger replaced by that of the glucocorticoid receptor. Comparison of AR-binding events in epididymides and prostates of wild-type (wt) and SPARKI mice revealed that AR achieves selective chromatin binding through a less stringent sequence requirement for the 3'-hexamer. In particular, a T at position 12 in the second hexamer is dispensable for wt AR but mandatory for SPARKI AR binding, and only a G at position 11 is highly conserved among wt AR-preferred response elements. Genome-wide AR-binding events agree with the respective transcriptome profiles, in that attenuated AR binding in SPARKI mouse epididymis correlates with blunted androgen response in vivo. Collectively, AR-selective actions in vivo rely on relaxed rather than increased stringency of cis-elements on chromatin. These elements are, in turn, poorly recognized by other class I steroid receptors.
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