Androgen receptor uses relaxed response element stringency for selective chromatin binding and transcriptional regulation in vivo.
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.
Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, FI-00014 Helsinki, Finland and Department of Cellular and Molecular Medicine, Molecular Endocrinology Laboratory, Katholieke Universiteit Leuven, Campus Gasthuisberg, BE-3000 Leuven, Belgium.
Biswajyoti
B
Sahu
Päivi
P
Pihlajamaa
Vanessa
V
Dubois
Stefanie
S
Kerkhofs
Frank
F
Claessens
Olli A
OA
Jänne
D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D004822:Epididymis / Q000378:metabolism; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014158:Transcription, Genetic
D002843:Chromatin; D011944:Receptors, Androgen