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Analyses of long-range interactions of the NR0B1 (DAX1) promoter using chromosome conformation capture-on-chip

ABSTRACT: Heterozygous point mutations or genomic deletions of NR0B1 in Xp21.2 result in congenital adrenal hypoplasia and hypogonadotropic hypogonadism, whereas the NR0B1 locus duplications in XY individuals lead to gonadal dysgenesis and a male-to-female dosage-sensitive sex reversal. We previously reported an ~ 257 kb deletion mapping 11 kb upstream to NR0B1 in a XY female with primary amenorrhea, small immature uterus, and gonadal dysgenesis pointing to an alteration of its regulatory region. To identify the potential regulatory elements of NR0B1, we have analyzed its 2 Mb flanking regions using chromosome conformation capture-on-chip (4C) in Sertoli cells and lymphoblasts. We confirm the involvement of the previously proposed regulatory region in the control of NR0B1 expression and describe several novel potential chromatin interactions within the NR0B1 locus that may be involved in sex differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE64470 | GEO | 2014/12/24

SECONDARY ACCESSION(S): PRJNA271087

REPOSITORIES: GEO

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Analyses of long-range interactions of the NR0B1 (DAX1) promoter using chromosome conformation capture-on-chip

Project description:Heterozygous point mutations or genomic deletions of NR0B1 in Xp21.2 result in congenital adrenal hypoplasia and hypogonadotropic hypogonadism, whereas the NR0B1 locus duplications in XY individuals lead to gonadal dysgenesis and a male-to-female dosage-sensitive sex reversal. We previously reported an ~ 257 kb deletion mapping 11 kb upstream to NR0B1 in a XY female with primary amenorrhea, small immature uterus, and gonadal dysgenesis pointing to an alteration of its regulatory region. To identify the potential regulatory elements of NR0B1, we have analyzed its 2 Mb flanking regions using chromosome conformation capture-on-chip (4C) in Sertoli cells and lymphoblasts. We confirm the involvement of the previously proposed regulatory region in the control of NR0B1 expression and describe several novel potential chromatin interactions within the NR0B1 locus that may be involved in sex differentiation. Custom designed 3x720K tiling microarrays covering 4 Mb region (chrX:28,082,100-32,087,100) flanking NR0B1 gene of interest

2014-12-24 | E-GEOD-64470 | biostudies-arrayexpress

Variants in SART3 cause a novel spliceosomopathy characterised by failure of testis development and neuronal defects

Project description:Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA binding protein that regulates a diverse array of biological processes, including recycling small nuclear ribonucleic acids (snRNAs) back to the spliceosome. Here we describe nine individuals from six independent families with a multisystem disorder, characterised by intellectual disability, developmental delay, brain anomalies and 46, XY-specific gonadal dysgenesis, who harbour recessive variants in the SART3 gene. Knockdown of the fly orthologue of SART3, Rnp4f, demonstrates a conserved role in neuronal and testicular development. Human induced pluripotent stem cells (iPSCs) carrying patient SART3 variants have disrupted neuronal and gonadal differentiation in vitro. These iPSCs have significant disruption to multiple signalling pathways and complexes, including spliceosome components and mRNA splicing. We propose that biallelic variants in the SART3 gene underlie a novel spliceosomopathy characterised by neuronal defects and testicular dysgenesis.

2023-06-11 | PXD032816 | Pride

New candidate gene identification for controlling mammalian gonadal sex determination

2009-11-09 | GSE18211 | GEO

Genomics of sexual cell fate transdifferentiation in the mouse gonad

Project description:Sex determination in mammals hinges on a cell fate decision in the fetal bipotential gonad between male Sertoli cells and female granulosa cells. While this decision normally is permanent, loss of key cell fate regulators such as the transcription factors Dmrt1 and Foxl2 can cause postnatal transdifferentiation from Sertoli to granulosa-like or vice versa. Here we examine the mechanism of transdifferentiation in mice carrying either a null mutation of Dmrt1 or a point mutation, R111G, that alters the DNA binding motif and causes human XY gonadal dysgenesis and sex reversal. We first define genes misexpressed during transdifferentiation and then show that female transcriptional regulators driving transdifferentiation in the mutant XY gonad (ESR2, LRH1, FOXL2) bind chromatin sites related to those normally bound in the XX ovary. We then define gene expression changes at the onset of transdifferentiation and abnormal chromatin compartments that may help destabilize cell fate and initiate transdifferentiation. We model the R111G mutation in mice and show that it causes dominant gonadal dysgenesis, analogous to its human phenotype but less severe. We show that R111G partially feminizes the testicular transcriptome and causes dominant disruption of DMRT1 binding specificity in vivo. These data help illuminate how transdifferentiation occurs when sexual cell fate maintenance is disrupted and identify chromatin sites and transcripts that may play key roles in the transdifferentiation process.

2022-09-30 | GSE208106 | GEO

Transcription profiling of mouse embryonic day (E) 11.5 and E12.5 mouse gonadsNew candidate gene identification for controlling mammalian gonadal sex determination

Project description:Mammalian gonadal sex determination is dependent on proper expression of sex determining genes in fetal gonadal somatic support cells (i.e., pre-granulosa and pre-Sertoli cells in XX and XY gonads, resp.). We used a unique transgenic mouse strain combined with microarray profiling to identify all the differentially expressed transcripts in XX and XY isolated somatic support cells during critical stages of gonadal development and differentiation. Experiment Overall Design: XX and XY somatic support cells (SSC) were isolated by flow cytometry from embryonic day (E) 11.5 and E12.5 mouse gonads. Total RNA was isolated from pools of isolated cells; 3 pools per sex and each timepoint.

2009-11-13 | E-GEOD-18211 | biostudies-arrayexpress

Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex: RNA-Seq Data

Project description:Sex differences in the brain as they relate to health and disease are often overlooked in experimental models. Many neurological disorders, like Alzheimer’s disease (AD), multiple sclerosis (MS), and autism, differ in prevalence between males and females. Sex differences originate either from differential gene expression on sex chromosomes or from hormonal differences, either directly or indirectly. To disentangle the relative contributions of genetic sex (XX v. XY) and gonadal sex (ovaries v. testes) to the regulation of hippocampal sex effects, we use the “sex-reversal” Four Core Genotype (FCG) mouse model which uncouples sex chromosome complement from gonadal sex. Transcriptomic and epigenomic analyses of hippocampal RNA and DNA from ∼12 month old FCG mice, reveals differential regulatory effects of sex chromosome content and gonadal sex on X- versus autosome-encoded gene expression and DNA modification patterns. Gene expression and DNA methylation patterns on the X chromosome were driven primarily by sex chromosome content, not gonadal sex. The majority of DNA methylation changes involved hypermethylation in the XX genotypes (as compared to XY) in the CpG context, with the largest differences in CpG islands, promoters, and CTCF binding sites. Autosomal gene expression and DNA modifications demonstrated regulation by sex chromosome complement and gonadal sex. These data demonstrate the importance of sex chromosomes themselves, independent of hormonal status, in regulating hippocampal sex effects. Future studies will need to further interrogate specific CNS cell types, identify the mechanisms by which sex chromosome regulate autosomes, and differentiate organizational from activational hormonal effects.

2022-01-31 | GSE184098 | GEO

Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex: Whole Genome OXBS-Seq Data

2022-01-31 | GSE184013 | GEO

gonads gene expression profiling in WT and Sox9flox/flox; Sf1:creTr/+ mice

Project description:In mammals, gonadal differentiation is the first step of sex determination, and the transcription factor Sox9 promotes testis differentiation. Here we used the XY Sox9flox/flox; Sf1:creTr/+ mouse model and show that the lack of Sox9 expression induces a full sex reversal of E13.5 XY Sox9flox/flox; Sf1:creTr/+ gonads compared to XY Sox9flox/flox. Keywords: gonads gene expression profiling in WT and Sox9flox/flox; Sf1:creTr/+ mice

2011-11-01 | GSE21650 | GEO

Transcription profiling of wild type and XY Nrg1 knock out male pooled embryonic gonads to decipher the role of this gene in sexual differentiation

Project description:In mammals, sex determination depends on the paternal transmission of the Y chromosome, which bears the Sry gene. At the time of sex determination, Sry becomes up-regulated in XY gonads initiating the expression of various factors required for testicular development. Most of these factors remain to be identified. As a consequence, the genetic causes of gonadal dysgenesis in human patients, other than those involving SRY, remain unknown. We found that Nrg1 is a new gene involved in early testicular development. To study the role of Nrg1 in embryonic testicular differentiation, conditional inactivation of Nrg1 was achieved with the help of a Wt1-Cre line. Mutant mice show defects of testis development. In order to correlate the defects of cellular processes and the misregulated gene network(s), expression profiles were examined in controls and mutants testes at 13.5 dpc. Each testis sample was pooled from eight embryos.

2017-10-02 | E-MTAB-5772 | biostudies-arrayexpress

Steroidogenic factor 1 (NR5A1) induces multiple transcriptional changes during differentiation of human gonadal-like cells

Project description:Nuclear receptor subfamily 5 group A member 1 (NR5A1) encodes steroidogenic factor 1 (SF1), a key regulatory factor that determines gonadal development and coordinates endocrine functions. Here, we have established a stem cell-based model of human gonadal development and applied it to evaluate the effects of NR5A1 during the transition from bipotential gonad to testicular cells. We combined directed differentiation of human induced pluripotent stem cells (46,XY) with activation of endogenous NR5A1 expression by conditionally-inducible CRISPR activation. The resulting male gonadal-like cells expressed several Sertoli cell transcripts, secreted anti-Müllerian hormone and responded to follicle-stimulating hormone by producing sex steroid intermediates. These characteristics were not induced without NR5A1 activation. A total of 2691 differentially expressed genetic elements, including both coding and non-coding RNAs, were detected immediately following activation of NR5A1 expression. Of those, we identified novel gonad-related putative NR5A1 targets, such as SCARA5, which we validated also by immunocytochemistry. In addition, NR5A1 activation was associated with dynamic expression of multiple gonad- and infertility-related differentially expressed genes. In conclusion, by combining targeted differentiation and endogenous activation of NR5A1 we have for the first time, been able to examine in detail the effects of NR5A1 in early human gonadal cells. The model and results obtained provide a useful resource for future investigations exploring the causative reasons for gonadal dysgenesis and infertility in humans.

2022-10-25 | GSE186606 | GEO

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