Rett syndrome is a severe neurodevelopmental disorder. In more than 90% of the patients, MECP2
alterations are present. However, in atypical Rett Syndrome, a MECP2 alteration can only be found
in 50-70% of the cases. Alterations in MEF2C and FOXG1 have also been implicated in typical and
atypical Rett Syndrome. Both genes present with a specific spatiotemporal expression pattern. This
strict regulation suggests an important role for regulatory sequences at these loci.
Interestingly, several deletions as well as translocations 5’to MEF2C have been reported in patients
with Rett-like manifestations. The same holds true for FOXG1, where several deletions 3’to FOXG1
have been described in patients with (a)typical Rett Syndrome. As these aberrations solely affect
noncoding regions, this is indicative of deletion/translocation of a crucial regulatory element.
Using 4C-seq we already identified 11 putative regulatory regions for MEF2C (6) & FOXG1 (5). The
aim of this project is to further validate these elements. To do this, we will assess both the in vivo &
in vitro activity pattern of the putative regulatory sequences and determine whether these regions
are transcribed as enhancer RNAs (eRNAs). This will give us valuable information on the regulation
of these genes. This project fits within a larger comprehensive project in which the regulatory
landscape of both genes is fully studied also using other state-of-the-art techniques such as 4C-seq
& CRISPR-Cas9 genome engineering.