Gonadal developmental genetics
3D genome topology and multi-omics in granulosa cells to decipher
the regulation of FOXL2
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FOXL2 is a key transcription factor in ovarian development and maintenance throughout life. Despite advanced knowledge about its role, its transcriptional regulation in the ovary is poorly understood. Most of the insights into FOXL2 regulation come from non-coding genetic defects we found in our patient cohort with blepharophimosis syndrome (BPES), a rare, autosomal dominant syndromic form of primary ovarian insufficiency (POI), and from a goat and mouse model.
We aim to answer outstanding key questions on the 3D topology and regulatory landscape of the FOXL2 region in human ovarian granulosa cells (GCs) using C-technologies and multi-omics, and to understand the impact of non-coding defects of the FOXL2 region on 3D topology and molecular pathways in BPES disease models. Key objectives are: (1) To map the 3D genome topology and regulatory landscapes in human GCs using C-technologies and multi-omics (2) To functionally validate ovarian cCREs and lncRNAs of the FOXL2 region (3) To determine the impact of non-coding deletions of the FOXL2 region on 3D topology and expression in BPES disease models. Overall, this work will advance genomic studies of more frequent ovarian diseases such as POI, occurring in 1% of the female population. |
This project is being carried out by PhD student Charlotte Matton and supervised by Prof. Dr. Elfride De Baere and Dr. Ir. Eva D'haene. The project is funded by an FWO fundamental research fellowship (2023-2027). |
Solve DSD: solving missing heritabillity in differences of sex development, using second and third next generation sequencing
This project is being carried out by PhD student Dr. Hannes Syryn and supervised by Prof. Dr. Elfride De Baere and Dr. Martine Cools. The project is funded by BESPEED (Belgian Society for pediatric endocrinology and diabetology). |
Differences of sex development (DSD) represent a group of rare conditions that occur with an estimated incidence of 1 in 4,500 births. Despite the implementation of whole exome sequencing (WES), a molecular diagnosis is missing in over 65% of DSD cases. It is our main goal to solve missing heritability in DSD using second and third generation whole genome sequencing (WGS). First, we will assess WES data beyond the DSD panel and perform WES-based copy number variant assessment in unsolved DSD patients from different centers in Belgium and Luxembourg that previously underwent targeted WES in a clinical context and in a consanguineous Iranian cohort with unsolved DSD. Second, we aim to identify missing pathogenic variants through second generation WGS. Third, we will search for cryptic structural variants through third generation WGS. Our multidisciplinary and cutting-edge approach combined with a strong track record in DSD and the proposed collaboration in a (trans)national network offer a unique opportunity to address unmet needs to accelerate the genetic diagnosis and to understand the underlying mechanisms of DSD. Our findings will be translated into guidelines for state-of-the-art genetic testing in DSD. We further expect to valorize our research findings by transferring them to the clinic and by closing the diagnostic gap, allowing correct patient-oriented management of care, paving the way to precision medicine in DSD.
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