title: Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia.
abstract: Mutations in IKBKAP, encoding a subunit of Elongator, cause familial dysautonomia (FD), a severe neurodevelopmental 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.
authors.affiliation: Laboratory of Medical Chemistry and Human Genetics, Center for Biomedical Integrative Genoproteomics, University of Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Close
authors.forename: Nicola
authors.initials: N
authors.lastname: Hawkes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cornez
authors.forename: Catherine
authors.initials: C
authors.lastname: Creppe
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lambert
authors.forename: Bernard
authors.initials: B
authors.lastname: Rogister
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Merville
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.forename: Jesper Q
authors.initials: JQ
authors.lastname: Svejstrup
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
mesh_terms: D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D004402:Dysautonomia, Familial / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D006657:Histones; D035602:Transcriptional Elongation Factors; D012319:RNA Polymerase II