[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Close, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Hawkes, Nicola; Cancer Research London Research Institute - UK > Clare Hall Laboratories
Lambert, Charles A; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire des tissus conjonctifs
Rogister, Bernard ; Université de Liège - ULiège > 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 - ULiège > Département de pharmacie > Chimie médicale
Slaugenhaupt, Susan A; Harvard Medical School > Massachusetts General Hospital > Center for Human Genetic Research
Bours, Vincent ; Université de Liège - ULiège > 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 - ULiège > Département de pharmacie > Chimie médicale
Language :
English
Title :
Transcription impairment and cell migration defects in elongator-depleted cells: Implication for familial dysautonomia
Publication date :
May 2006
Journal title :
Molecular Cell
ISSN :
1097-2765
eISSN :
1097-4164
Publisher :
Cell Press, Cambridge, United States - Massachusetts
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