Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD

L.D. Goodman; M. Prudencio; N.J. Kramer; L.F. Martinez-Ramirez; A.R. Srinivasan; M. Lan; M.J. Parisi; Y. Zhu; J. Chew; C.N. Cook; A. Berson; A.D. Gitler; L. Petrucelli; N.M. Bonini

doi:10.1038/s41593-019-0396-1

Journal article

Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD

L.D. Goodman, M. Prudencio, N.J. Kramer, L.F. Martinez-Ramirez, A.R. Srinivasan, M. Lan, M.J. Parisi, Y. Zhu, J. Chew, C.N. Cook, …

Nature Neuroscience, Vol.22(6), pp.863-874

2019

DOI: https://doi.org/10.1038/s41593-019-0396-1

PMID: 31110321

Abstract

Animals

C9orf72 Protein

DNA Repeat Expansion

Drosophila melanogaster

Frontotemporal Dementia

Gene Expression Regulation

Humans

Mice

Nuclear Proteins

Transcription Factors

heterodimer

RNA polymerase II

guanine nucleotide exchange C9orf72

LEO1 protein, human

nuclear protein

PAF1 protein, human

repetitive DNA

transcription factor

adult

amino acid repeat

animal experiment

animal model

animal tissue

Article

brain degeneration

C9orf72 gene

chromatin

clinical feature

complex formation

controlled study

female

frontotemporal degeneration

gene

gene expression regulation

gene knockdown

genetic association

genetic transcription

genome

human

human tissue

LEO1 gene

major clinical study

male

middle aged

mouse

nonhuman

PAF1 gene

priority journal

sequence analysis

animal

Drosophila melanogaster

frontotemporal dementia

genetics

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. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Title: Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD
Creators: L.D. Goodman - University of Pennsylvania
M. Prudencio - Mayo Clinic in Florida
N.J. Kramer - Stanford University
L.F. Martinez-Ramirez - University of Pennsylvania
A.R. Srinivasan - University of Pennsylvania
M. Lan - University of Pennsylvania
M.J. Parisi - University of Pennsylvania
Y. Zhu - University of Pennsylvania
J. Chew - Mayo Clinic in Florida
C.N. Cook - Mayo Clinic in Florida
A. Berson - University of Pennsylvania
A.D. Gitler - Stanford University
L. Petrucelli - Mayo Clinic in Florida
N.M. Bonini - University of Pennsylvania
Publication Details: Nature Neuroscience, Vol.22(6), pp.863-874
Publisher: Nature Publishing Group; BERLIN
Number of pages: 18
Grant note: Transgenic RNAi Project at Harvard Medical School: NIH/NIGMS R01-GM084947 Systems and Integrative Biology NIH/NIGMS training grant: T32-GM07517 NIH/NINDS: R35-NS097263, R35-NS097273, P01-NS084974, P01-NS099114, R01-NS078283, R35-NS09727 Mayo Clinic FoundationALS AssociationRobert Packard Center for ALS Research at Johns HopkinsTarget ALS FoundationNational Institute of Neurological Disorders and Stroke: R35NS097273, P01NS099114, R35NS097275, R35NS097263 National Institute on Aging: P01NS084974
The authors thank A. T. Moehlman and H. Kramer 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.).
Comment: Export Date: 27 February 2026; Cited By: 60; CODEN: NANEF
Academic Unit: Level 02 - Executives; Executives; UMMG Department of Neurology
Resource Type: Journal article
PMID: 31110321
Record Identifier: 991032996191602976