TY - JOUR
T1 - Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD
AU - Goodman, Lindsey D.
AU - Prudencio, Mercedes
AU - Kramer, Nicholas J.
AU - Martinez-Ramirez, Luis F.
AU - Srinivasan, Ananth R.
AU - Lan, Matthews
AU - Parisi, Michael J.
AU - Zhu, Yongqing
AU - Chew, Jeannie
AU - Cook, Casey N.
AU - Berson, Amit
AU - Gitler, Aaron D.
AU - Petrucelli, Leonard
AU - Bonini, Nancy M.
N1 - Funding Information:
The authors thank A. T. Moehlman and H. Krämer at UT Southwestern for ERG investigations and T. Gendron for GP studies in (G4C2)n animals post-screening. J. T. Lis, P. Gallant, and M. Buszczak generously shared valuable Drosophila reagents targeting dPAF1C. Additional thanks are given to E. B. Lee, T. A. Jongens, Z. Zhou, and members of the Bonini Laboratory, notably, J. Kennerdell, L. McGurk, and J. Saikumar, for helpful comments. Undergraduates D. P. Cerza and A. Chen provided minimal technical support. The authors thank the Transgenic RNAi Project at Harvard Medical School (NIH/NIGMS R01-GM084947) and the VDRC for developing transgenic RNAi fly stocks used in this study. Appreciation is also given to the NINDS Human Cell and Data Repository at Rutgers University for fibroblast cells. This work was funded by the Systems and Integrative Biology NIH/NIGMS training grant T32-GM07517 (to L.D.G.), NIH/NINDS R35-NS097263 (to A.D.G.), NIH/NINDS R35-NS097273 (to L.P.), NIH/ NINDS P01-NS084974 (to L.P.), NIH/NINDS P01-NS099114 (to L.P.), Mayo Clinic Foundation (to L.P.), ALS Association (to L.P. and M.P.), Robert Packard Center for ALS Research at Johns Hopkins (to L.P.), Target ALS Foundation (to L.P.), NIH/NINDS R01-NS078283 (to N.M.B.), and NIH/NINDS R35-NS09727 (to N.M.B.).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)30+) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9+). Through an unbiased large-scale screen of (G4C2)49-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)30+ transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2)30+ expression in flies and mice. In humans, PAF1 is also upregulated in C9+-derived cells, and its heterodimer partner, LEO1, binds C9+ repeat chromatin. In C9+ FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9+ FTD.
AB - An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)30+) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9+). Through an unbiased large-scale screen of (G4C2)49-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)30+ transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2)30+ expression in flies and mice. In humans, PAF1 is also upregulated in C9+-derived cells, and its heterodimer partner, LEO1, binds C9+ repeat chromatin. In C9+ FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9+ FTD.
UR - http://www.scopus.com/inward/record.url?scp=85066075621&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066075621&partnerID=8YFLogxK
U2 - 10.1038/s41593-019-0396-1
DO - 10.1038/s41593-019-0396-1
M3 - Article
C2 - 31110321
AN - SCOPUS:85066075621
SN - 1097-6256
VL - 22
SP - 863
EP - 874
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 6
ER -