RevSex duplication-induced and sex-related differences in the<i>SOX9</i>regulatory region chromatin landscape in human fibroblasts

Lybæk, Helle; Bruijn, Diederik de; Dijk, Anke H.A. den Engelsman-van; Vanichkina, Darya; Nepal, Chirag; Brendehaug, Atle; Houge, Gunnar

doi:10.4161/epi.27474

Cited by 17 publications

(14 citation statements)

References 31 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In their scenario, the addition of a third copy causes local chromatin alteration, allowing this third copy to escape the repressive ‘female’ chromatin environment and to adopt a permissive ‘male’ chromatin state, resulting in activation of putative testis-specific enhancers within the RevSex/XXSR region, leading to upregulation of SOX9 . In support of this, a recent study reported that the RevSex duplication in a 46,XX DSD individual was associated with a more open chromatin signature as also observed in male but not female controls 34. However, as this study was performed on primary fibroblasts, it may not reflect the state of early gonadal Sertoli or granulosa cells.…”

Section: Discussionmentioning

confidence: 72%

Copy number variation of two separate regulatory regions upstream ofSOX9causes isolated 46,XY or 46,XX disorder of sex development

et al. 2015

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 72%

Copy number variation of two separate regulatory regions upstream ofSOX9causes isolated 46,XY or 46,XX disorder of sex development

et al. 2015

View full text Add to dashboard Cite

show abstract

“…As hypothesized by Lybaek and colleagues, the RevSex element may interact with other known regulatory elements of SOX9 such as the TESCO motif or the minimal promoter region of SOX9 . In a study of a familial case of XX sex‐reversal carrying a 148 kb RevSex duplication, the chromatin landscape at the TESCO enhancer element was found to be modified in cells from XX masculinized individuals [Lybæk et al, ]. The authors speculate that the RevSex duplication was acting to induce long‐range epigenetic changes including a more open chromatin landscape at the TESCO element resulting in the upregulation of SOX9 expression.…”

Section: Discussionmentioning

confidence: 99%

Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD)

Hyon

Chantot‐Bastaraud

Harbuz

et al. 2015

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Disorders of Sex Development (DSD) are a heterogeneous group of disorders affecting gonad and/or genito-urinary tract development and usually the endocrine-reproductive system. A genetic diagnosis is made in only around 20% of these cases. The genetic causes of 46,XX-SRY negative testicular DSD as well as ovotesticular DSD are poorly defined. Duplications involving a region located ∼600 kb upstream of SOX9, a key gene in testis development, were reported in several cases of 46,XX DSD. Recent studies have narrowed this region down to a 78 kb interval that is duplicated or deleted respectively in 46,XX or 46,XY DSD. We identified three phenotypically normal patients presenting with azoospermia and 46,XX testicular DSD. Two brothers carried a 83.8 kb duplication located ∼600 kb upstream of SOX9 that overlapped with the previously reported rearrangements. This duplication refines the minimal region associated with 46,XX-SRY negative DSD to a 40.7-41.9 kb element located ∼600 kb upstream of SOX9. Predicted enhancer elements and evolutionary-conserved binding sites for proteins known to be involved in testis determination are located within this region.

show abstract

“…Altogether our data reinforce the role of the desert region upstream of SOX9 in the regulation of this gene, as indicated by an altered histone methylation signature demonstrated in one of the RevSex duplicated cases. 40 It is noteworthy that RevSex includes two lncRNAs, TCONS_00025195 and TCONS_00025196, with specific expression in the testis, 41 possibly having a role in SOX9 transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

View full text Add to dashboard Cite

Duplications in the~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects. European Journal of Human Genetics (2015) 23, 1025-1032; doi:10.1038/ejhg.2014.237; published online 5 November 2014 INTRODUCTION 46,XX disorders of sex development (DSDs) are congenital conditions in which, in the presence of a female karyotype, the development of gonadal and anatomical sex is atypical, ranging from various degrees of ambiguous genitalia to phenotypic males with azoospermia. These conditions are poorly characterized, at least in subjects whose DNA does not contain SRY, the gene triggering testis differentiation in mammals. 1 In fact, in most XX males, SRY is transposed to the tip of Xp as a consequence of a recurrent Xp;Yp translocation, arising predominantly by nonallelic homologous recombination between PRKX and PRKY on a particular Y haplotypic background. 2,3 These males, usually with small testes, are essentially picked up among men with nonobstructive azoospermia.A much less well-understood category is that of the 46,XX DSDs negative for SRY. Recently, six of these cases have been reported

show abstract

RevSex duplication-induced and sex-related differences in theSOX9regulatory region chromatin landscape in human fibroblasts

Cited by 17 publications

References 31 publications

Copy number variation of two separate regulatory regions upstream ofSOX9causes isolated 46,XY or 46,XX disorder of sex development

Copy number variation of two separate regulatory regions upstream ofSOX9causes isolated 46,XY or 46,XX disorder of sex development

Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD)

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

Contact Info

Product

Resources

About