Completion of the human genome project led to the post-genome era. Next
important task is to apply differences of genome information of each individual
to the personalized medicine. Non-synonymous single nucleotide polymorphisms
(SNPs) that result in amino acid changes in proteins were extensively studied.
However examples of variation in regulatory sequences are poorly reported,
although there are several examples of regulatory SNPs associated with disease susceptibility related to development and differentiation.
As a first step, we focused on retinoid X receptors (RXRs) which are members of the nuclear hormone receptor superfamily and act as
ligand-inducible transcription factors. A Ligand of RXR is 9-cis retinoic
acid that plays an important role in development, differentiation, and
homeostasis. Although RXRs are promiscuous dimerization partners for a
lot of nuclear receptors, RXRs also form homodimers whose molecular mechanisms
are largely unexplored. To identify RXR homodimer-binding sites in the
human genome, we performed a modified yeast one-hybrid system [J Recept Signal Transduct Res. 2010 Apr;30(2):88-105, Methods Mol Biol. 2013;977:125-36] and identified the human genomic fragments with putative RXR homodimer-binding sites. By electrophoresis mobility shift assays, the interaction between human RXR homodimer and the putative binding sites in the obtained genomic fragment. In addition, We identified single nucleotide polymorphisms on the RXR homodimer-binding sites which altered the RXR homodimer-DNA binding affinities. We hope that these results provide insights into the molecular mechanisms underlying the physiological and pathological actions of RXRs. |
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