The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles.
The Forkhead transcription factor FOXL2 plays a crucial role in ovarian development and maintenance. In humans, its mutations lead to craniofacial abnormalities, isolated or associated with ovarian dysfunction. Using a combinatorial approach, we identified and characterized a FoxL2 response element (FLRE) and showed that it is highly specific and that it diverges from that of other Forkhead transcription factors. This specificity should prevent aberrant regulation of FOXL2 targets by other members of the family and should prevent ectopic activation of the ovarian differentiation program in testes. We provide evidence that the FLRE is used in naturally occurring promoters. We show that polyAlanine expansions of FOXL2, which are the most frequent pathogenic mutations, induce a length-dependent loss of response on different artificial promoter reporters depending on the number and sequence of the FLREs that they contain. Thus, we provide clear mechanistic evidence explaining how the architecture of promoters influences their sensitivity to decreased transcription factor availability. Furthermore, we speculate that the generally absent ovarian phenotype of patients carrying the most frequent polyAlanine expansion should come from its ability to properly regulate high-affinity ovarian targets. The existence of critical high-affinity ovarian targets would be compatible with the role of FOXL2 in reproduction and ensure developmental and functional robustness. Taken together, our results give mechanistic insights on the molecular pathogenesis of FOXL2 polyAlanine expansions.
Benayoun
Bérénice A
BA
INSERM U567, Team 21, Département de Génétique et Développement, Institut Cochin 75014, Paris, France.
Caburet
Sandrine
S
Dipietromaria
Aurélie
A
Bailly-Bechet
Marc
M
Batista
Frank
F
Fellous
Marc
M
Vaiman
Daniel
D
Veitia
Reiner A
RA
D000483:Alleles; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010053:Ovary / Q000254:growth & development / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D014162:Transfection; D019680:Trinucleotide Repeat Expansion
C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D010455:Peptides; D011994:Recombinant Proteins; C019529:polyalanine; D004247:DNA