Lambert, Charles A[Université de Liège - ULg > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs >]
Rogister, Bernard[Université de Liège - ULg > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine >]
Siebenlist, Ulrich[National Institute of Health - Bethesda Mariland > National Inst. of Allergy and infectious disease > Laboratory of Immunoregulation > >]
Merville, Marie-Paule[Université de Liège - ULg > Département de pharmacie > Chimie médicale >]
Slaugenhaupt, Susan A[Harvard Medical School > Massachusetts General Hospital > Center for Human Genetic Research > >]
Bours, Vincent[Université de Liège - ULg > Département des sciences biomédicales et précliniques > Génétique générale et humaine]
Svejstrup, Jesper Q[Cancer Research UK London Research Institute > Clare Hall laboratories > > >]
Chariot, Alain[Université de Liège - ULg > Département de pharmacie > Chimie médicale >]
[en] Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neuro-developmental disease with complex clinical characteristics. Elongator was previously linked not only with transcriptional elongation and histone acetylation but also with other cellular processes. Here, we used RNA interference (RNAi) and fibroblasts from FD patients to identify Elongator target genes and study the role of Elongator in transcription. Strikingly, whereas Elongator is recruited to both target and nontarget genes, only target genes display histone H3 hypoacetylation and progressively lower RNAPII density through the coding region in FD cells. Interestingly, several target genes encode proteins implicated in cell motility. Indeed, characterization of IKAP/hELP1 RNAi cells, FD fibroblasts, and neuronal cell-derived cells uncovered defects in this cellular function upon Elongator depletion. These results indicate that defects in Elongator function affect transcriptional elongation of several genes and that the ensuing cell motility deficiencies may underlie the neuropathology of FD patients.
[Université de Liège - ULg > Département de pharmacie > Chimie médicale >]
