Divergent Single Cell Transcriptome and Epigenome Alterations in ALS and FTD Patients with C9orf72 Mutation

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Sep 15

PMID 37714849

Authors

Junhao Li

Manoj K Jaiswal

Jo-Fan Chien

Alexey Kozlenkov

Jinyoung Jung

Ping Zhou

Mahammad Gardashli

Luc J Pregent

Erica Engelberg-Cook

Dennis W Dickson

Veronique V Belzil

Eran A Mukamel

Stella Dracheva

Affiliations

Soon will be listed here.

Abstract

A repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we investigate single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9-ALS, C9-FTD, and control donors. C9-ALS donors present pervasive alterations of gene expression with concordant changes in chromatin accessibility and histone modifications. The greatest alterations occur in upper and deep layer excitatory neurons, as well as in astrocytes. In neurons, the changes imply an increase in proteostasis, metabolism, and protein expression pathways, alongside a decrease in neuronal function. In astrocytes, the alterations suggest activation and structural remodeling. Conversely, C9-FTD donors have fewer high-quality neuronal nuclei in the frontal cortex and numerous gene expression changes in glial cells. These findings highlight a context-dependent molecular disruption in C9-ALS and C9-FTD, indicating unique effects across cell types, brain regions, and diseases.

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References

Freibaum B, Lu Y, Lopez-Gonzalez R, Kim N, Almeida S, Lee K . GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015; 525(7567):129-33. PMC: 4631399. DOI: 10.1038/nature14974. View

Mariga A, Mitre M, Chao M . Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease. Neurobiol Dis. 2016; 97(Pt B):73-79. PMC: 5295364. DOI: 10.1016/j.nbd.2016.03.009. View

Li J, Jaiswal M, Chien J, Kozlenkov A, Jung J, Zhou P . Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation. Nat Commun. 2023; 14(1):5714. PMC: 10504300. DOI: 10.1038/s41467-023-41033-y. View

Renton A, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs J . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72(2):257-68. PMC: 3200438. DOI: 10.1016/j.neuron.2011.09.010. View

Khakh B, Sofroniew M . Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015; 18(7):942-52. PMC: 5258184. DOI: 10.1038/nn.4043. View

Granja J, Corces M, Pierce S, Bagdatli S, Choudhry H, Chang H . ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat Genet. 2021; 53(3):403-411. PMC: 8012210. DOI: 10.1038/s41588-021-00790-6. View

Smith E, Shaw P, De Vos K . The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. 2017; 710:132933. DOI: 10.1016/j.neulet.2017.06.052. View

Vahsen B, Gray E, Thompson A, Ansorge O, Anthony D, Cowley S . Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers. Nat Rev Neurol. 2021; 17(6):333-348. DOI: 10.1038/s41582-021-00487-8. View

Zhang Y, Chen K, Sloan S, Bennett M, Scholze A, OKeeffe S . An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34(36):11929-47. PMC: 4152602. DOI: 10.1523/JNEUROSCI.1860-14.2014. View

10.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

11.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

12.

Dekker S, Kampinga H, Bergink S . DNAJs: more than substrate delivery to HSPA. Front Mol Biosci. 2015; 2:35. PMC: 4485348. DOI: 10.3389/fmolb.2015.00035. View

13.

Phatnani H, Guarnieri P, Friedman B, Carrasco M, Muratet M, OKeeffe S . Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci U S A. 2013; 110(8):E756-65. PMC: 3581928. DOI: 10.1073/pnas.1222361110. View

14.

Ross-Innes C, Stark R, Teschendorff A, Holmes K, Ali H, Dunning M . Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012; 481(7381):389-93. PMC: 3272464. DOI: 10.1038/nature10730. View

15.

Wang J, Duncan D, Shi Z, Zhang B . WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013; 41(Web Server issue):W77-83. PMC: 3692109. DOI: 10.1093/nar/gkt439. View

16.

Zappia L, Oshlack A . Clustering trees: a visualization for evaluating clusterings at multiple resolutions. Gigascience. 2018; 7(7). PMC: 6057528. DOI: 10.1093/gigascience/giy083. View

17.

Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G . A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2011; 11(1):54-65. DOI: 10.1016/S1474-4422(11)70261-7. View

18.

Ling S, Polymenidou M, Cleveland D . Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013; 79(3):416-38. PMC: 4411085. DOI: 10.1016/j.neuron.2013.07.033. View

19.

Bakken T, Jorstad N, Hu Q, Lake B, Tian W, Kalmbach B . Comparative cellular analysis of motor cortex in human, marmoset and mouse. Nature. 2021; 598(7879):111-119. PMC: 8494640. DOI: 10.1038/s41586-021-03465-8. View

20.

Abramzon Y, Fratta P, Traynor B, Chia R . The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Front Neurosci. 2020; 14:42. PMC: 7012787. DOI: 10.3389/fnins.2020.00042. View