The epigenetic profile of the SOX9 regulatory region appears Y chromosome dependent. G. Houge, H. Lybæk Center for medical genetics, Bergen, Norway.
Recently it was shown that duplications of the RevSex element, located 0.5 Mb upstream of SOX9, cause XX-DSD and deletions XY-DSD (DSD; disorder of sex development). To explore how a 148 kb RevSex duplication could have turned on gonadal SOX9 expression in the absence of SRY in an XX-male, we examined the chromatin landscape of the SOX9 regulatory region by custom ChIP-on-chip experiments in fibroblast lysates from the index, his RevSex duplication carrier father and six controls. In addition, regional CpG methylation was examined. The RevSex duplication was associated with chromatin changes that could have facilitated the establishment of an auto-regulatory SOX9 self-maintaining loop through better accessibility of the TESCO enhancer 14-15 kb upstream of SOX9. Here a dip in the H3K9me3 signal was found together with a strong H3K4me3 profile towards the SOX9 transcription start site. A similar type of effect was found when three control males were compared to three control females. Like females, the XX-DSD case had an enhanced H3K27me3 profile in the100 kb region upstream of SOX9. The RevSex duplication carrier father had the most open chromatin profile of all. Our findings suggest that RevSex copy number-induced sex reversal could be due to long-range changes in chromatin conformation. Furthermore, the differences in chromatin state maps between males and females suggest that the Y chromosome may induce large-scale conformational changes of genomic regions. Our findings are preliminary, but give reason to further explore whether SRY regulates gene expression through regional epigenetic modification.
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