TY - JOUR
T1 - Sex reversal following deletion of a single distal enhancer of Sox9
AU - Gonen, Nitzan
AU - Futtner, Chris R.
AU - Wood, Sophie
AU - Alexandra Garcia-Moreno, S.
AU - Salamone, Isabella M.
AU - Samson, Shiela C.
AU - Sekido, Ryohei
AU - Poulat, Francis
AU - Maatouk, Danielle M.
AU - Lovell-Badge, Robin
N1 - Funding Information:
We dedicate this paper to the memory of Danielle M. Maatouk, a much-missed colleague. We are grateful to the Biological Research Facility, Genetic Modification Service, Advanced Sequencing Facility, and Experimental Histopathology Facility of the Francis Crick Institute and the Flow Cytometry Core at Northwestern University for technical assistance. We thank members of our labs for advice, support, and helpful comments. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001107), the U.K. Medical Research Council (FC001107), and the Wellcome Trust (FC001107), and by the U.K. Medical Research Council (U117512772). F.P. was funded by the Agence Nationale pour la Recherche (ANR blanc TestisDev). D.M.M. was funded by the Northwestern University School of Medicine.
Publisher Copyright:
© 2017 The Authors.
PY - 2018/6/29
Y1 - 2018/6/29
N2 - Cell fate decisions require appropriate regulation of key genes. Sox9, a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer 13 (Enh13), a 557–base pair element located 565 kilobases 5′ from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.
AB - Cell fate decisions require appropriate regulation of key genes. Sox9, a direct target of SRY, is pivotal in mammalian sex determination. In vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing revealed several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer 13 (Enh13), a 557–base pair element located 565 kilobases 5′ from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Our data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within a 32.5-kilobase region whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans.
KW - UKRI
KW - MRC
UR - http://www.scopus.com/inward/record.url?scp=85048629730&partnerID=8YFLogxK
UR - https://abdn.pure.elsevier.com/en/publications/sex-reversal-following-deletion-of-a-single-distal-enhancer-ofi-s
U2 - 10.1126/science.aas9408
DO - 10.1126/science.aas9408
M3 - Article
C2 - 29903884
AN - SCOPUS:85048629730
SN - 0036-8075
VL - 360
SP - 1469
EP - 1471
JO - Science
JF - Science
IS - 6396
ER -