TY - JOUR

T1 - Transcription Impairment and Cell Migration Defects in Elongator-Depleted Cells

T2 - Implication for Familial Dysautonomia

AU - Close, Pierre

AU - Hawkes, Nicola

AU - Cornez, Isabelle

AU - Creppe, Catherine

AU - Lambert, Charles A.

AU - Rogister, Bernard

AU - Siebenlist, Ulrich

AU - Merville, Marie Paule

AU - Slaugenhaupt, Susan A.

AU - Bours, Vincent

AU - Svejstrup, Jesper Q.

AU - Chariot, Alain

N1 - Funding Information: The authors are grateful to Dr. K. Brown for help generating the anti-IKAP antibody and to Dr. L. van Parijs for the gift of the pLL3.7 construct. Fabrizia Cesca and Giampietro Schiavo are thanked for help with aspects of the work on cell migration. Work in the Chariot lab was supported by grants from the University of Liège, TELEVIE, the Centre Anti-Cancéreux, and the Belgian Federation against Cancer. Work in the Svejstrup lab was supported by a grant from the Familial Dysautonomia Foundation and by an in-house grant from Cancer Research UK.

PY - 2006/5/19

Y1 - 2006/5/19

N2 - 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.

AB - 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.

KW - DNA

KW - HUMDISEASE

U2 - 10.1016/j.molcel.2006.04.017

DO - 10.1016/j.molcel.2006.04.017

M3 - Journal article

C2 - 16713582

AN - SCOPUS:33745034833

VL - 22

SP - 521

EP - 531

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 4

ER -