{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:05:24Z","timestamp":1792785924995,"version":"4.5.0"},"reference-count":139,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2020,5,1]],"date-time":"2020-05-01T00:00:00Z","timestamp":1588291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"European Union\u2019s Horizon 2020 Research and Innovation Programme","award":["825100 to P.A.F. and S.M.G."],"award-info":[{"award-number":["825100 to P.A.F. and S.M.G."]}]},{"name":"European Community\u2019s Seventh Framework Programme","award":["212885 to PAF"],"award-info":[{"award-number":["212885 to PAF"]}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L010011\/1 to PAF"],"award-info":[{"award-number":["MR\/L010011\/1 to PAF"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"French National Research Agency","doi-asserted-by":"publisher","award":["ANR n\u00b0 16-CE14-0017-02 and n\u00b018-CE14-0038-02 to F.C"],"award-info":[{"award-number":["ANR n\u00b0 16-CE14-0017-02 and n\u00b018-CE14-0038-02 to F.C"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["SNF n\u00b0 CRS115_171007 to B.J."],"award-info":[{"award-number":["SNF n\u00b0 CRS115_171007 to B.J."]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"French School of Public Health"},{"DOI":"10.13039\/501100007525","name":"University of Rennes 1","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007525","id-type":"DOI","asserted-by":"publisher"}]},{"name":"French National Institute of Health and Medical Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>Which transcriptional program triggers sex differentiation in bipotential gonads and downstream cellular events governing fetal testis and ovary development in humans?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>The characterization of a dynamically regulated protein-coding and non-coding transcriptional landscape in developing human gonads of both sexes highlights a large number of potential key regulators that show an early sexually dimorphic expression pattern.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>Gonadal sex differentiation is orchestrated by a sexually dimorphic gene expression program in XX and XY developing fetal gonads. A comprehensive characterization of its non-coding counterpart offers promising perspectives for deciphering the molecular events underpinning gonad development and for a complete understanding of the etiology of disorders of sex development in humans.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>To further investigate the protein-coding and non-coding transcriptional landscape during gonad differentiation, we used RNA-sequencing (RNA-seq) and characterized the RNA content of human fetal testis (N\u2009=\u200924) and ovaries (N\u2009=\u200924) from 6 to 17 postconceptional week (PCW), a key period in sex determination and gonad development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>First trimester fetuses (6\u201312 PCW) and second trimester fetuses (13\u201314 and 17 PCW) were obtained from legally induced normally progressing terminations of pregnancy. Total RNA was extracted from whole human fetal gonads and sequenced as paired-end 2\u2009\u00d7\u200950 base reads. Resulting sequences were mapped to the human genome, allowing for the assembly and quantification of corresponding transcripts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>This RNA-seq analysis of human fetal testes and ovaries at seven key developmental stages led to the reconstruction of 22\u2009080 transcripts differentially expressed during testicular and\/or ovarian development. In addition to 8935 transcripts displaying sex-independent differential expression during gonad development, the comparison of testes and ovaries enabled the discrimination of 13\u2009145 transcripts that show a sexually dimorphic expression profile. The latter include 1479 transcripts differentially expressed as early as 6 PCW, including 39 transcription factors, 40 long non-coding RNAs and 20 novel genes. Despite the use of stringent filtration criteria (expression cut-off of at least 1 fragment per kilobase of exon model per million reads mapped, fold change of at least 2 and false discovery rate adjusted P values of less than &amp;lt;1%), the possibility of assembly artifacts and of false-positive differentially expressed transcripts cannot be fully ruled out.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LARGE-SCALE DATA<\/jats:title>\n                    <jats:p>Raw data files (fastq) and a searchable table (.xlss) containing information on genomic features and expression data for all refined transcripts have been submitted to the NCBI GEO under accession number GSE116278.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>The intrinsic nature of this bulk analysis, i.e. the sequencing of transcripts from whole gonads, does not allow direct identification of the cellular origin(s) of the transcripts characterized. Potential cellular dilution effects (e.g. as a result of distinct proliferation rates in XX and XY gonads) may account for a few of the expression profiles identified as being sexually dimorphic. Finally, transcriptome alterations that would result from exposure to pre-abortive drugs cannot be completely excluded. Although we demonstrated the high quality of the sorted cell populations used for experimental validations using quantitative RT-PCR, it cannot be totally excluded that some germline expression may correspond to cell contamination by, for example, macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>For the first time, this study has led to the identification of 1000 protein-coding and non-coding candidate genes showing an early, sexually dimorphic, expression pattern that have not previously been associated with sex differentiation. Collectively, these results increase our understanding of gonad development in humans, and contribute significantly to the identification of new candidate genes involved in fetal gonad differentiation. The results also provide a unique resource that may improve our understanding of the fetal origin of testicular and ovarian dysgenesis syndromes, including cryptorchidism and testicular cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This work was supported by the French National Institute of Health and Medical Research (Inserm), the University of Rennes 1, the French School of Public Health (EHESP), the Swiss National Science Foundation [SNF n\u00b0 CRS115_171007 to B.J.], the French National Research Agency [ANR n\u00b0 16-CE14-0017-02 and n\u00b0 18-CE14-0038-02 to F.C.], the Medical Research Council [MR\/L010011\/1 to P.A.F.] and the European Community\u2019s Seventh Framework Programme (FP7\/2007-2013) [under grant agreement no 212885 to P.A.F.] and from the European Union\u2019s Horizon 2020 Research and Innovation Programme [under grant agreement no 825100 to P.A.F. and S.M.G.]. There are no competing interests related to this study.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humrep\/deaa041","type":"journal-article","created":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T15:13:12Z","timestamp":1582038792000},"page":"1099-1119","source":"Crossref","is-referenced-by-count":39,"title":["Dynamics of the transcriptional landscape during human fetal testis and ovary development"],"prefix":"10.1093","volume":"35","author":[{"given":"Estelle","family":"Lecluze","sequence":"first","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) - UMR_S 1085, F-35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine D","family":"Rolland","sequence":"first","affiliation":[{"name":"Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sant\u00e9, environnement et travail) - UMR_S 1085, F-35000 Rennes, 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