Integrated analysis of the role of transcription factor SF-1/NR5A1 and its dosage-dependent target genes in gonadal function and disorders of sex development (DSD) – Goldilocks
Integrated analysis of the role of transcription factor SF-1/NR5A1 et its dosage-dependent target genes in gonadal function and disorders of sexual development (DSD)
The transcription factor Steroidogenic Factor 1 (SF-1; NR5A1 in the official nomenclature) has a pivotal role in adrenogonadal development. Mutations in NR5A1 account for 10-20% of DSD with known genetic diagnosis. tTght regulation of SF-1 dosage is at the heart of the mechanism how this transcription factor regulates gene expression and perturbations thereof have important pathological consequences.
Mechanisms of dosage-dependent gene regulation by SF-1
Our project has the following aims: <br />Aim 1: To acquire deeper mechanistic insight into the role of SF-1 functional dosage in gonadal development and function. <br />For this aim, we will take advantage of a new animal model we have developed, where SF-1 expression is selectively increased in tissues expressing its endogenous transcript. In addition, we will investigate the role of new cofactors modulating SF-1 transcriptional activity, with special interest in RNA-binding proteins and RNA species. <br />Aim 2: To understand how novel genes involved in the SF-1 functional network identified in Aim 1 can cause DSD and increase the diagnostic yield in DSD.<br />Based on the surprisingly variable phenotypes displayed by individuals bearing NR5A1 mutations, even inside the same family, an oligogenic mode of inheritance has been hypothesized where variants in other genes involved in the sex determination process would contribute to each patient’s phenotype.
- Analysis of gonadal development and function in the Sf-1:Cre-Nr5a1 LSL mouse line.
- Mapping of SF-1 genomic binding sites by ChIP-seq in mouse gonads under basal and increased expression conditions.
- Identification of SF-1 dosage-dependent target genes in mouse gonads by single-cell RNA-seq.
- Functional analysis of the effects of DAX-1 and its interactors upon gene expression and RNA metabolism.
- Analysis of SF-1 binding sites and SF-1 dose-dependent target genes in a large cohort of DSD cases.
- Functional analysis of variants potentially associated with human DSD.
- Modelling variants associated with DSD in a novel human cellular model.
The results of our project will considerably increase the number of candidate target genes with a potential pathogenetic role in DSD since it will provide an exhaustive list of the SF-1 dosage-dependent target genes and of new cofactors able to regulate its activity.
The results of our project are predicted:
- to significantly advance our understanding of the molecular mechanisms underpinning the phenotypic effects of SF-1 functional dosage in gonadal development and function;
- to identify new genes responsible for human DSD, with important impact on classification, diagnosis and possibly therapy of these disorders.
In progress.
Steroidogenic Factor 1 (SF-1/NR5A1) has a pivotal role in adrenogonadal development. Patients harbouring NR5A1 mutations present a wide range of phenotypes involving gonadal, and more rarely adrenal, development and function. Conversely, SF-1 overexpression is associated with adrenocortical tumourigenesis. These data show that precise regulation of SF-1 dosage is at the heart of the mechanism how this transcription factor regulates gene expression. The aims of our project are focused on better understanding the molecular mechanisms how SF-1 dosage-dependently regulates gene expression and gonadal differentiation in vivo and to search for pathological variants of SF-1 dosage-dependent target genes and cofactors in patients with DSD, followed by their functional characterization. Our results will unravel novel features of dosage-dependent gene regulation by SF-1 and identify new genetic causes of DSD, with important impact on disease classification, diagnosis and possibly therapy.
Project coordination
Enzo LALLI (Institut de Pharmacologie Moléculaire et Cellulaire)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
IPMC Institut de Pharmacologie Moléculaire et Cellulaire
Unité Génétique du Développement Humain - Institut Pasteur
Help of the ANR 535,560 euros
Beginning and duration of the scientific project:
January 2021
- 36 Months
