C9orf72 ALS Model Mice: Right On the Epigenetic Mark?

Chemical changes in the genome may contribute to ALS (Belzil et al., 2016). But how to develop therapies that reset these genetic switches in models of the disease is tricky to do. Reprogramming motor neurons from people with ALS may rewrite and/or erase at least some of these epigenetic marks, while impacting repeat stability (Mertens et al., 2015; Cohen-Hadad et al., 2016; Almeida et al., 2013). And, animal models of ALS may not fully recapitulate them.

C9orf72 ALS, Run by 5hmc? The hypermethylation of the promoter of the C9orf72 gene may help protect motor neurons by reducing the synthesis of potentially toxic dipeptide repeat proteins and repeat-containing RNAs (see April 2015 news; McMillan et al., 2015, Liu et al., 2014). Increased demethylation however, may derepress their synthesis and thereby contribute to motor neuron toxicity in the disease.[Cohen-Hadad et al., 2016 under CC BY 4.0 license.]

Now, a research team led by the University of Miami’s Zane Zeier in Florida reports that a mouse model of C9orf72 ALS exhibits key epigenetic changes in the brain associated with the disease. These chemical changes include increased levels of 5-hydroxymethylcytosine (5hmC) at the expanded promoter of the C9orf72 gene; key chemical changes that may lead to more dipeptide repeat proteins and repeat-containing RNAs which may contribute to the disease (see January 2017 conference news; Esanov et al., 2016).

The study is published on June 12 in Molecular Neurodegeneration.

The expanded promoter of the C9orf72 gene also exhibited increased hypermethylation including trimethylation of histone H3’s lysine 9 (H3K9) according to chromatin immunoprecipitation (ChIP)-based analysis. This increased methylation may help protect motor neurons in at least some people with C9orf72 ALS by reducing the production of dipeptide repeat proteins and repeat-containing RNAs (see April 2015 news; McMillan et al., 2015, Liu et al., 2014).

The mouse model, developed by Robert Brown and colleagues at the University of Massachusetts Medical Center, lacks motor symptoms but exhibits key hallmarks of the disease, including the synthesis of dipeptide repeat proteins and repeat-containing RNAs (see December 2015 news; Peters et al, 2015).

The findings build on previous studies, led by Zane Zeier, which found that increased levels of 5hmC could be detected in post-mortem brain tissue of some people with C9orf72 ALS (Esanov et al., 2016). These epigenetic changes, which occur during the process of DNA demethylation, may derepress the C9orf72 gene, thereby enabling the production of dipeptide repeat proteins and repeat-containing RNAs (see January 2017 conference news).

Together, the results suggest that drugs that erase these epigenetic marks may help treat C9orf72 ALS, in part by reducing levels of dipeptide repeat proteins and repeat-containing RNAs which may contribute to motor neuron toxicity by multiple mechanisms (see August 2015, March 2017, June 2017 news; Cooper-Knock et al., 2014; Freibaum et al., 2015; Zhang et al., 2015; Jovičić et al., 2015; Yin et al., 2017; Boeynaems et al., 2017).

Now, Zeier’s team hopes to identify potential treatment strategies that may reset these genetic switches in hopes to protect motor neurons in people with C9orf72 ALS and FTD (see Zeier et al., 2015). Stay tuned.

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To learn more about the emerging role of epigenetics in C9orf72 ALS, check out our recent coverage of the ENCALS satellite meeting in Dublin, Ireland: ALS Researchers Tackle Epigenetics of C9ORF72 and the Entire Genome.

Featured Paper

Esanov R, Cabrera GT, Andrade NS, Gendron TF, Brown RH Jr, Benatar M, Wahlestedt C, Mueller C, Zeier Z. A C9ORF72 BAC mouse model recapitulates key epigenetic perturbations of ALS/FTD. Mol Neurodegener. 2017 Jun 12;12(1):46. [PubMed]

References

Esanov R, Belle KC, van Blitterswijk M, Belzil VV, Rademakers R, Dickson DW, Petrucelli L, Boylan KB, Dykxhoorn DM, Wuu J, Benatar M, Wahlestedt C, Zeier Z. C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Exp Neurol. 2016 Mar;277:171-7. [PubMed]

McMillan CT, Russ J, Wood EM, Irwin DJ, Grossman M, McCluskey L, Elman L, Van Deerlin V, Lee EB.  C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence. Neurology. 2015 Apr 21;84(16):1622-30. [PubMed]

Liu EY, Russ J, Wu K, Neal D, Suh E, McNally AG, Irwin DJ, Van Deerlin VM, Lee EB. C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol. 2014 Oct;128(4):525-41. [PubMed]

Peters OM, Cabrera GT, Tran H, Gendron TF, McKeon JE, Metterville J, Weiss A, Wightman N, Salameh J, Kim J, Sun H, Boylan KB, Dickson D, Kennedy Z, Lin Z, Zhang YJ, Daughrity L, Jung C, Gao FB, Sapp PC, Horvitz HR, Bosco DA, Brown SP, de Jong P, Petrucelli L, Mueller C, Brown RH Jr. Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron. 2015 Dec 2;88(5):902-9. [PubMed]

Cohen-Hadad Y, Altarescu G, Eldar-Geva T, Levi-Lahad E, Zhang M, Rogaeva E, Gotkine M, Bartok O, Ashwal-Fluss R, Kadener S, Epsztejn-Litman S, Eiges R. Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells. Stem Cell Reports. 2016 Nov 8;7(5):927-940. [PubMed].

Further Reading

Finch NA, Wang X, Baker MC, Heckman MG, Gendron TF, Bieniek KF, Wuu J, DeJesus-Hernandez M, Brown PH, Chew J, Jansen-West KR, Daughrity LM, Nicholson AM, Murray ME, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Petrucelli L, Boeve BF, Graff-Radford NR, Asmann YW, Dickson DW, Benatar M, Bowser R, Boylan KB, Rademakers R, van Blitterswijk M. Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers. Neurol Genet. 2017 Jun 7;3(4):e161. [PubMed].

Belzil VV, Katzman RB, Petrucelli L. ALS and FTD: an epigenetic perspective. Acta Neuropathol. 2016 Oct;132(4):487-502. [PubMed].

Mertens J, Paquola AC, Ku M, Hatch E, Böhnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR, Gonçalves JT, Toda T, Kim Y, Winkler J, Yao J, Hetzer MW, Gage FH. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell. 2015 Dec 3;17(6):705-18. [PubMed].

 

 

 

5hmc c9orf72 disease-als disease-ftd epigenetics methylation neuroprotection topic-genetics topic-randd topic-researchmodels
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