Dissection of the cis-regulatory landscape of FOXL2

01 January 2016 → 31 December 2018
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Medical imaging and therapy
    • Medical imaging and therapy
    • Medical imaging and therapy
Project description

The strictly regulated expression of most developmental genes is dependent on cis-regulatory elements (CREs) such as enhancers. Studies of individuals with a genetic disease lacking coding mutations in the associated disease gene but with a nearby non-coding genetic defect, also called cis-ruptions, provided many insights into this. An example of this is the FOXL2 gene, encoding a forkhead transcription factor playing a role in ovarian development and having a crucial anti-testis function in the adult ovary. The identification of translocations and deletions upstream of FOXL2 in blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated with premature ovarian failure (POF), revealed this is a cis-ruption disease and hinted towards a strict regulation of its expression in the periocular mesenchyme and in fetal and adult ovaries. Previous studies of BPES cases with cis-regulatory defects revealed several CREs with enhancer capacities. The tissue-specific cis-regulation of FOXL2 remains largely unexplored however. Here we aim (i) to characterize the cis-regulatory landscape of FOXL2 in ovary granulosa cells; and (ii) to uncover noncoding defects in FOXL2-associated CREs in a unique discovery cohort of molecularly unexplained BPES cases. More insights into ovary-specific CREs of FOXL2 might be relevant for more frequent ovarian diseases such as non-syndromic POF and polycystic ovary syndrome.