Repeat Expansion Affects Both Transcription Initiation and Elongation in Friedreich Ataxia Cells

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Dec 4

PMID 21127046

Citations 48

Authors

Daman Kumari

Rea Erika Biacsi

Karen Usdin

Affiliations

Soon will be listed here.

Abstract

Expansion of a GAA · TTC repeat in the first intron of the frataxin (FXN) gene causes an mRNA deficit that results in Friedreich ataxia (FRDA). The region flanking the repeat on FRDA alleles is associated with more extensive DNA methylation than is seen on normal alleles and histone modifications typical of repressed genes. However, whether these changes are responsible for the mRNA deficit is controversial. Using chromatin immunoprecipitation and cell lines from affected and unaffected individuals, we show that certain marks of active chromatin are also reduced in the promoter region of the FXN gene in patient cells. Thus, the promoter chromatin may be less permissive for transcription initiation than it is on normal alleles. Furthermore, we show that the initiating form of RNA polymerase II and histone H3 trimethylated on lysine 4, a chromatin mark tightly linked to transcription initiation, are both present at lower levels on FRDA alleles. In addition, a mark of transcription elongation, trimethylated H3K36, shows a reduced rate of accumulation downstream of the repeat. Our data thus suggest that repeat expansion reduces both transcription initiation and elongation in FRDA cells. Our findings may have implications for understanding the mechanism responsible for FRDA as well as for therapeutic approaches to reverse the transcription deficit.

Citing Articles

The Regulation of the Disease-Causing Gene .

Dong Y, Mercado-Ayon E, Coulman J, Flatley L, Ngaba L, Adeshina M Cells. 2024; 13(12.

PMID: 38920668 PMC: 11202134. DOI: 10.3390/cells13121040.

Advances in Nucleotide Repeat Expansion Diseases: Transcription Gets in Phase.

Figueiredo A, Loureiro J, Macedo-Ribeiro S, Silveira I Cells. 2023; 12(6).

PMID: 36980167 PMC: 10047669. DOI: 10.3390/cells12060826.

Perspectives on current models of Friedreich's ataxia.

Kelekci S, Yildiz A, Sevinc K, Cimen D, Onder T Front Cell Dev Biol. 2022; 10:958398.

PMID: 36036008 PMC: 9403045. DOI: 10.3389/fcell.2022.958398.

Premature transcription termination at the expanded GAA repeats and aberrant alternative polyadenylation contributes to the Frataxin transcriptional deficit in Friedreich's ataxia.

Li Y, Li J, Wang J, Zhang S, Giles K, Prakash T Hum Mol Genet. 2022; 31(20):3539-3557.

PMID: 35708503 PMC: 9558844. DOI: 10.1093/hmg/ddac134.

DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.

Rodden L, Gilliam K, Lam C, Rojsajjakul T, Mesaros C, Dionisi C Sci Rep. 2022; 12(1):5031.

PMID: 35322126 PMC: 8943190. DOI: 10.1038/s41598-022-09002-5.

References

Herman D, Jenssen K, Burnett R, Soragni E, Perlman S, Gottesfeld J . Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat Chem Biol. 2006; 2(10):551-8. DOI: 10.1038/nchembio815. View

Sakamoto N, Chastain P, Parniewski P, Ohshima K, Pandolfo M, Griffith J . Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich's ataxia. Mol Cell. 1999; 3(4):465-75. DOI: 10.1016/s1097-2765(00)80474-8. View

Smale S, Baltimore D . The "initiator" as a transcription control element. Cell. 1989; 57(1):103-13. DOI: 10.1016/0092-8674(89)90176-1. View

Mishina M, Kurosaki T, Yamamoto T, Notake M, Masu M, Numa S . DNA sequences required for transcription in vivo of the human corticotropin-beta-lipotropin precursor gene. EMBO J. 1982; 1(12):1533-8. PMC: 553247. DOI: 10.1002/j.1460-2075.1982.tb01351.x. View

Punga T, Buhler M . Long intronic GAA repeats causing Friedreich ataxia impede transcription elongation. EMBO Mol Med. 2010; 2(4):120-9. PMC: 3377279. DOI: 10.1002/emmm.201000064. View

Campuzano V, Montermini L, Molto M, Pianese L, Cossee M, Cavalcanti F . Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996; 271(5254):1423-7. DOI: 10.1126/science.271.5254.1423. View

Filippova G, Thienes C, Penn B, Cho D, Hu Y, Moore J . CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet. 2001; 28(4):335-43. DOI: 10.1038/ng570. View

Strausberg R, Feingold E, Grouse L, Derge J, Klausner R, Collins F . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A. 2002; 99(26):16899-903. PMC: 139241. DOI: 10.1073/pnas.242603899. View

Bidichandani S, Ashizawa T, Patel P . The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am J Hum Genet. 1998; 62(1):111-21. PMC: 1376805. DOI: 10.1086/301680. View

10.

Stock J, Giadrossi S, Casanova M, Brookes E, Vidal M, Koseki H . Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nat Cell Biol. 2007; 9(12):1428-35. DOI: 10.1038/ncb1663. View

11.

Greene E, Mahishi L, Entezam A, Kumari D, Usdin K . Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res. 2007; 35(10):3383-90. PMC: 1904289. DOI: 10.1093/nar/gkm271. View

12.

Hirakata M, Okano Y, Pati U, Suwa A, Medsger Jr T, Hardin J . Identification of autoantibodies to RNA polymerase II. Occurrence in systemic sclerosis and association with autoantibodies to RNA polymerases I and III. J Clin Invest. 1993; 91(6):2665-72. PMC: 443330. DOI: 10.1172/JCI116505. View

13.

Brookes E, Pombo A . Modifications of RNA polymerase II are pivotal in regulating gene expression states. EMBO Rep. 2009; 10(11):1213-9. PMC: 2775184. DOI: 10.1038/embor.2009.221. View

14.

Lorincz M, Dickerson D, Schmitt M, Groudine M . Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat Struct Mol Biol. 2004; 11(11):1068-75. DOI: 10.1038/nsmb840. View

15.

Grabczyk E, Usdin K . The GAA*TTC triplet repeat expanded in Friedreich's ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner. Nucleic Acids Res. 2000; 28(14):2815-22. PMC: 102661. DOI: 10.1093/nar/28.14.2815. View

16.

Biacsi R, Kumari D, Usdin K . SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome. PLoS Genet. 2008; 4(3):e1000017. PMC: 2265469. DOI: 10.1371/journal.pgen.1000017. View

17.

Li K, Besse E, Ha D, Kovtunovych G, Rouault T . Iron-dependent regulation of frataxin expression: implications for treatment of Friedreich ataxia. Hum Mol Genet. 2008; 17(15):2265-73. PMC: 2465796. DOI: 10.1093/hmg/ddn127. View

18.

Al-Mahdawi S, Mouro Pinto R, Ismail O, Varshney D, Lymperi S, Sandi C . The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues. Hum Mol Genet. 2007; 17(5):735-46. DOI: 10.1093/hmg/ddm346. View

19.

Xu C, Soragni E, Chou C, Herman D, Plasterer H, Rusche J . Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing. Chem Biol. 2009; 16(9):980-9. PMC: 2909763. DOI: 10.1016/j.chembiol.2009.07.010. View

20.

Wang P, Lin C, Smith E, Guo H, Sanderson B, Wu M . Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol. 2009; 29(22):6074-85. PMC: 2772563. DOI: 10.1128/MCB.00924-09. View