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Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington’s disease

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Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded trinucleotide CAG repeat in the gene coding for huntingtin. Deregulation of chromatin remodeling is linked to the pathogenesis of HD but the mechanism remains elusive. To identify what genes are deregulated by trimethylated histone H3K9 (H3K9me3)-dependent heterochromatin, we performed H3K9me3-ChIP genome-wide sequencing combined with RNA sequencing followed by platform integration analysis in stable striatal HD cell lines (STHdhQ7/7 and STHdhQ111/111) cells. We found that genes involving neuronal synaptic transmission including cholinergic receptor M1 (CHRM1), cell motility, and neuronal differentiation pathways are downregulated while their promoter regions are highly occupied with H3K9me3 in HD. Moreover, we found that repression of CHRM1 gene expression by H3K9me3 impairs Ca2+-dependent neuronal signal transduction in stable cell lines expressing mutant HD protein. Thus, our data indicate that the epigenetic modifications, such as aberrant H3K9me3-dependent heterochromatin plasticity, directly contribute to the pathogenesis of HD.

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References

  1. Bonner TI, Buckley NJ, Young AC, Brann MR (1987) Identification of a family of muscarinic acetylcholine receptor genes. Science 237:527–532

    Article  PubMed  CAS  Google Scholar 

  2. Calabresi P, Centonze D, Gubellini P, Pisani A, Bernardi G (2000) Acetylcholine-mediated modulation of striatal function. Trends Neurosci 23:120–126

    Article  PubMed  CAS  Google Scholar 

  3. Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L, Davies SW, Penney JB, Bates GP, Young AB (1998) Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene. Proc Natl Acad Sci USA 95:6480–6485

    Article  PubMed  CAS  Google Scholar 

  4. Ekins S, Nikolsky Y, Bugrim A, Kirillov E, Nikolskaya T (2007) Pathway map** tools for analysis of high content data. Methods Mol Biol 356:319–350

    PubMed  CAS  Google Scholar 

  5. Fujita PA, Rhead B, Zweig AS, Hinrichs AS, Karolchik D, Cline MS, Goldman M, Barber GP, Clawson H, Coelho A, Diekhans M, Drezer TR, Giardine BM, Harte RA, Hillman-Jackson J, Hsu F, Kirkup V, Kuhn RM, Learmed K, Li CH, Meyer LR, Pohl A, Raney BJ, Rosenbloom KR, Smith KE, Haussler D, Kent WJ (2011) The UCSC Genome Browser database: update 2011. Nucleic Acids Res 39:D876–D882

    Article  PubMed  CAS  Google Scholar 

  6. Gardian G, Browne SE, Choi DK, Klivenyi P, Gregorio J, Kubilus JK, Ryu H, Langley B, Ratan RR, Ferrante RJ, Beal MF (2005) Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease. J Biol Chem 280:556–563

    PubMed  CAS  Google Scholar 

  7. Grewal SI, Jia S (2007) Heterochromatin revisited. Nat Rev Genet 8:35–46

    Article  PubMed  CAS  Google Scholar 

  8. Hake SB, **ao A, Allis CD (2004) Linking the epigenetic language of covalent histone modifications to cancer. Br J Cancer 90:761–769

    Article  PubMed  CAS  Google Scholar 

  9. da Huang W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57

    Article  CAS  Google Scholar 

  10. Hulme EC, Birdsall NJM, Buckley NJ (1990) Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30:633–673

    Article  PubMed  CAS  Google Scholar 

  11. Junker BH, Koschutzki D, Schreiber F (2006) Exploration of biological network centralities with CentiBiN. BMC Bioinformatics 7:219

    Article  PubMed  Google Scholar 

  12. Lee J, Hagerty S, Cormier KA, Kung AL, Ferrante RJ, Ryu H (2008) Monoallele deletion of CBP leads to pericentromeric heterochromatin condensation through ESET expression and histone H3 (K9) methylation. Hum Mol Genet 17:1774–1782

    Article  PubMed  CAS  Google Scholar 

  13. Lim D, Fedrizzi L, Tartari M, Zuccato C, Cattaneo E, Brini M, Carafoli E (2008) Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem 283:5780–5789

    Article  PubMed  CAS  Google Scholar 

  14. Milakovic T, Quintanilla RA, Johnson GV (2006) Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem 281:34785–34795

    Article  PubMed  CAS  Google Scholar 

  15. Mortazavi A, Williams BA (2008) Map** and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5:621–628

    Article  PubMed  CAS  Google Scholar 

  16. Pisani A, Bernardi G, Ding J, Surmeier DJ (2007) Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci 30:545–553

    Article  PubMed  CAS  Google Scholar 

  17. Ryu H, Lee J, Impey S, Ratan RR, Ferrante RJ (2005) Antioxidants modulate mitochondrial protein kinase A and increase CREB binding to D-Loop DNA of the mitochondrial genome in neurons. Proc Natl Acad Sci USA 102:13915–13920

    Article  PubMed  CAS  Google Scholar 

  18. Ryu H, Lee J, Hagerty SW, Soh BY, McAlpin SE, Cormier KA, Smith KM, Ferrante RJ (2006) ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington’s disease. Proc Natl Acad Sci USA 103:19176–19181

    Article  PubMed  CAS  Google Scholar 

  19. Sadri-Vakili G, Cha JH (2006) Mechanisms of disease: histone modifications in Huntington’s disease. Nat Clin Pract Neurol 2:330–338

    Article  PubMed  CAS  Google Scholar 

  20. Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ 3rd (2002) SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev 16:919–932

    Article  PubMed  CAS  Google Scholar 

  21. Shannon P, Markiel A, Qzier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504

    Article  PubMed  CAS  Google Scholar 

  22. Stack EC, Del Signore SJ, Luthi-Carter R, Soh BY, Goldstein DR, Matson S, Goodrich S, Markey AL, Cormier K, Hagerty SW, Smith K, Ryu H, Ferrante RJ (2007) Modulation of nucleosome dynamics in Huntington’s disease. Hum Mol Genet 16:1164–1175

    Article  PubMed  CAS  Google Scholar 

  23. Sugita S, Uchimura N, Jiang ZG, North RA (1991) Distinct muscarinic receptors inhibit release of GABA and excitatory amino acids in mammalian brain. Proc Natl Acad Sci USA 88:2608–2611

    Article  PubMed  CAS  Google Scholar 

  24. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983

    Article  Google Scholar 

  25. Trettel F, Rigamonti D, Hilditch-Maguire P, Wheeler VC, Sharp AH, Persichetti F, Cattaneo E, MacDonald ME (2000) Dominant phenotypes produced by the HD mutation in STHdh (Q111) striatal cell. Hum Mol Genet 9:2799–2809

    Article  PubMed  CAS  Google Scholar 

  26. Wang H, An W, Cao R, **a L, Erdjument-Bromage H, Chatton B, Tempst P, Roeder RG, Zhang Y (2003) mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol Cell 12:475–487

    Article  PubMed  CAS  Google Scholar 

  27. Wang Z, Kai L, Day M, Ronesi J, Yin HH, Ding J, Tkatch T, Locinger DM, Surmeier DJ (2006) Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons. Neuron 50:443–452

    Article  PubMed  CAS  Google Scholar 

  28. Wess J (1996) Molecular biology of muscarinic acetylcholine receptors. Crit Rev Neurobiol 10:69–99

    Article  PubMed  CAS  Google Scholar 

  29. Wilson CJ (2006) Striatal D2 receptors and LTD: yes, but not where you thought they were. Neuron 50:347–348

    Article  PubMed  CAS  Google Scholar 

  30. Wu R, Terry AV, Singh PB, Gilbert DM (2005) Differential subnuclear localization and replication timing of histone H3 lysine 9 methylation states. Mol Biol Cell 16:2872–2881

    Article  PubMed  CAS  Google Scholar 

  31. Wu R, Singh PB, Gilbert DM (2006) Uncoupling global and fine-tuning replication timing determinants for mouse pericentric heterochromatin. J Cell Biol 174:185–194

    Article  PubMed  CAS  Google Scholar 

  32. Wu TD, Nacu S (2010) Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 26:873–881

    Article  PubMed  CAS  Google Scholar 

  33. Yamada M, Sato T, Shimohata T, Hayashi S, Igarashi S, Tsuji S, Takahashi H (2001) Interaction between neuronal intranuclear inclusions and promyelocytic leukemia protein nuclear and coiled bodies in CAG repeat diseases. Am J Pathol 159:1785–1795

    Article  PubMed  CAS  Google Scholar 

  34. Yang L, **a L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y (2002) Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene 21:148–152

    Article  PubMed  CAS  Google Scholar 

  35. Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev 15:2343–2360

    Article  PubMed  CAS  Google Scholar 

  36. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE et al (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9:R137

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank to Dr. Marcy MacDonald for STHdhQ7/7 and STHdhQ111/111 cells and to Min-Kyung Jung for her technical assistance. This study was supported by WCU Neurocytomics Program Grant (800-20080848) (H.R.) and SRC Grant (2010-0029-403) (H.R.) from MEST of Korea, Flagship Grant (H.R.) from KIST and NIH NS 067283-01A1 (H.R.).

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Authors and Affiliations

  1. Veteran’s Affairs Boston Healthcare System, Boston, MA, 02130, USA

    Junghee Lee, Neil W. Kowall & Hoon Ryu

  2. Department of Neurology and Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, 02118, USA

    Junghee Lee, Neil W. Kowall & Hoon Ryu

  3. WCU Neurocytomics Group, Seoul National University College of Medicine, Seoul, South Korea

    Yu ** Hwang, Won-Chul Lee, Ki Yoon Kim & Hoon Ryu

  4. Genome Medicine Institute, Seoul National University College of Medicine, Seoul, South Korea

    Jong-Yeon Shin, Won-Chul Lee & Jong-Il Kim

  5. Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea

    **hong Wie & Insuk So

  6. Psoma Therapeutics Inc, Seoul, South Korea

    Jong-Yeon Shin & Jong-Il Kim

  7. Department of Chemical Engineering and School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, South Korea

    Min Young Lee & Daehee Hwang

  8. Burke Medical Research Institute, White Plains, NY, USA

    Rajiv R. Ratan

  9. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, South Korea

    Ae Nim Pae

  10. Department of Neurology, Boston University School of Medicine, VA Boston Healthcare System, Building 1A, Rm109, 150 South Huntington Avenue, Boston, MA, 02130, USA

    Hoon Ryu

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  1. Junghee Lee
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Corresponding author

Correspondence to Hoon Ryu.

Additional information

J. Lee, Y. J. Hwang, J.-Y. Shin, W.-C. Lee, and J. Wie equally contributed to this work.

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Lee, J., Hwang, Y.J., Shin, JY. et al. Epigenetic regulation of cholinergic receptor M1 (CHRM1) by histone H3K9me3 impairs Ca2+ signaling in Huntington’s disease. Acta Neuropathol 125, 727–739 (2013). https://doi.org/10.1007/s00401-013-1103-z

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  • DOI: https://doi.org/10.1007/s00401-013-1103-z

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