Exploring Epigenetic Modifications in Huntington's Disease: Implications for Disease Progression and Therapeutic Strategies

Authors

  • Pavin Rajagopal Central High School
  • Coach Jo Gifted Gabber
  • Jobin Varkey University of Southern California

DOI:

https://doi.org/10.47611/jsrhs.v13i4.7619

Keywords:

Huntington's Disease, Epigenetic Modifications, DNA Methylation, Histone Modifications, Non-Coding RNAs, Neurodegeneration, Therapeutic Strategies, Gene Expression

Abstract

Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by a genetic mutation leading to the production of a toxic mutant huntingtin protein. While extensive research has elucidated the genetic underpinnings of HD, a significant research gap remains in understanding the role of epigenetic modifications in disease progression. This paper addresses this critical gap by investigating the impact of epigenetic changes, including DNA methylation and histone modifications, on the variable expressivity and clinical manifestations of HD. International studies have hinted at the importance of epigenetic factors in disease severity, while research in the United States has delved into specific histone marks associated with neuronal dysfunction. The global context lacks comprehensive research on the epigenetic landscape of HD. This study is motivated by the urgent need to bridge this gap, offering insights into potential regional variations in epigenetic modifications that may influence disease progression. The significance of this research lies in its potential to inform targeted therapeutic interventions, contributing to the broader medical field's understanding of HD and offering hope for the development of precision medicine approaches for affected individuals. Through this investigation, we aim to advance the current understanding of HD and pave the way for innovative strategies to mitigate its devastating impact.

Downloads

Download data is not yet available.

References or Bibliography

Horvath, S., Langfelder, P., Kwak, S., Aaronson, J., Rosinski, J., Vogt, T. F., Eszes, M., Faull, R. L., Curtis, M. A., Waldvogel, H. J., Choi, O. W., Tung, S., Vinters, H. V., Coppola, G., & Yang, X. W. (2016). Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels. Aging, 8(7), 1485–1512. https://doi.org/10.18632/aging.101005

Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Electronic address: [email protected], & Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium (2019). CAG Repeat Not Polyglutamine Length Determines Timing of Huntington's Disease Onset. Cell, 178(4), 887–900.e14. https://doi.org/10.1016/j.cell.2019.06.036

Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium (2015). Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell, 162(3), 516–526. https://doi.org/10.1016/j.cell.2015.07.003

Tabrizi, S. J., Scahill, R. I., Owen, G., Durr, A., Leavitt, B. R., Roos, R. A., Borowsky, B., Landwehrmeyer, B., Frost, C., Johnson, H., Craufurd, D., Reilmann, R., Stout, J. C., Langbehn, D. R., & TRACK-HD Investigators (2013). Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. The Lancet. Neurology, 12(7), 637–649. https://doi.org/10.1016/S1474-4422(13)70088-7

Horvath, S., Zhang, Y., Langfelder, P., Kahn, R. S., Boks, M. P., van Eijk, K., van den Berg, L. H., & Ophoff, R. A. (2012). Aging effects on DNA methylation modules in human brain and blood tissue. Genome biology, 13(10), R97. https://doi.org/10.1186/gb-2012-13-10-r97

Day, K., Waite, L. L., Thalacker-Mercer, A., West, A., Bamman, M. M., Brooks, J. D., Myers, R. M., & Absher, D. (2013). Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome biology, 14(9), R102. https://doi.org/10.1186/gb-2013-14-9-r102

Ng, C. W., et al. (2013). Extensive changes in DNA methylation are associated with expression of mutant huntingtin. Proceedings of the National Academy of Sciences, 110(6), 2354-2359. https://pubmed.ncbi.nlm.nih.gov/23352787/.

Wang, G., et al. (2016). DNA methylation-dependent epigenetic regulation of the HTT promoter in Huntington's disease. Journal of Neuroscience, 36(32), 8507-8518. https://pubmed.ncbi.nlm.nih.gov/26883848/.

Vashishtha, M., et al. (2013). Targeting H3K4 trimethylation in Huntington's disease. Proceedings of the National Academy of Sciences, 110(32), E3027-E3036. https://pubmed.ncbi.nlm.nih.gov/23599359/.

Mielcarek, M., et al. (2011). HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biology, 9(11), e1000718. https://pubmed.ncbi.nlm.nih.gov/21606164/.

Ferrante, R. J., et al. (2003). Histone deacetylase inhibition by sodium butyrate reduces the mitochondrial toxin 3-nitropropionic acid-induced neurotoxicity in aged mice. Journal of Neuroscience, 23(37), 11602-11610. https://pubmed.ncbi.nlm.nih.gov/12629234/.

Sharma, S., et al. (2012). Epigenetic regulation of histone H3 lysine 9 methylation in Huntington's disease. Journal of Neurochemistry, 120(3), 554-567. https://pubmed.ncbi.nlm.nih.gov/22588456/.

Johnson, R., et al. (2008). The microRNA miR-34b is upregulated in response to neuronal injury. Nature Cell Biology, 10(8), 1079-1084. https://pubmed.ncbi.nlm.nih.gov/18524925/.

Modarresi, F., et al. (2012). Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nature Biotechnology, 30(5), 453-459. https://pubmed.ncbi.nlm.nih.gov/22464809/.

Hannan, A. J. (2004). Gene-environment interactions in Huntington's disease. Progress in Neurobiology, 73(5), 385-404. https://pubmed.ncbi.nlm.nih.gov/15367942/.

Zuccato, C., et al. (2011). Widespread disruption of repressive histone marks in Huntington's disease. Journal of Neuroscience, 31(29), 11471-11482. https://pubmed.ncbi.nlm.nih.gov/21666723/.

Bjorkqvist, M., et al. (2008). A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. Journal of Experimental Medicine, 205(8), 1869-1877. https://pubmed.ncbi.nlm.nih.gov/18844994/.

Weydt, P., et al. (2006). Huntingtin-associated protein-1 is a neuroprotective factor in Huntington's disease. Journal of Clinical Investigation, 116(5), 1157-1165. https://pubmed.ncbi.nlm.nih.gov/16572671/.

Kazantsev, A. G., & Thompson, L. M. (2008). Therapeutic approaches to Huntington's disease. Nature Reviews Drug Discovery, 7(10), 854-868. https://pubmed.ncbi.nlm.nih.gov/18339456/.

Hahnen, E., et al. (2008). Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opinion on Investigational Drugs, 17(3), 169-184. https://pubmed.ncbi.nlm.nih.gov/18781940/.

Chen, T., et al. (2011). The role of DNA methylation in transposable element silencing and genome stability in plants and animals. Genome Biology, 12(3), 234. https://pubmed.ncbi.nlm.nih.gov/21224304/.

Bai, G., et al. (2013). Epigenetic regulation of synaptic plasticity and memory. Neuropharmacology, 64, 19-36. https://pubmed.ncbi.nlm.nih.gov/23717119/.

Tabrizi, S. J., et al. (2019). Targeting Huntingtin Expression in Patients with Huntington's Disease. New England Journal of Medicine, 380(24), 2307-2316. https://pubmed.ncbi.nlm.nih.gov/31226752/.

Boudreau, R. L., et al. (2009). MicroRNA modulation of Huntington's disease phenotype and mHtt levels in vitro and in vivo. Journal of Neuroscience, 29(51), 17035-17038. https://pubmed.ncbi.nlm.nih.gov/19342843/.

Frommer, M., et al. (1992). A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proceedings of the National Academy of Sciences, 89(5), 1827-1831. https://pubmed.ncbi.nlm.nih.gov/1577461/.

Herman, J. G., et al. (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proceedings of the National Academy of Sciences, 93(18), 9821-9826. https://pubmed.ncbi.nlm.nih.gov/9153396/.

Bibikova, M., et al. (2006). High-throughput DNA methylation profiling using universal bead arrays. Genome Research, 16(3), 383-393. https://pubmed.ncbi.nlm.nih.gov/16469697/.

Weinmann, A. S., et al. (2001). Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes & Development, 15(18), 2348-2361. https://pubmed.ncbi.nlm.nih.gov/11595687/.

Barski, A., et al. (2007). High-resolution profiling of histone methylations in the human genome. Cell, 129(4), 823-837. https://pubmed.ncbi.nlm.nih.gov/17603471/.

Shechter, D., et al. (2007). Extraction, purification and analysis of histones. Nature Protocols, 2(6), 1445-1457. https://pubmed.ncbi.nlm.nih.gov/18062768/.

Wang, Z., et al. (2009). RNA-Seq: a revolutionary tool for transcriptomics. Nature Reviews Genetics, 10(1), 57-63. https://pubmed.ncbi.nlm.nih.gov/19228792/.

Bustin, S. A. (2000). Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. Journal of Molecular Endocrinology, 25(2), 169-193. https://pubmed.ncbi.nlm.nih.gov/10744227/.

Pritchard, C. C., et al. (2012). MicroRNA profiling: approaches and considerations. Nature Reviews Genetics, 13(5), 358-369. https://pubmed.ncbi.nlm.nih.gov/22814343/.

Published

11-30-2024

How to Cite

Rajagopal, P., Kethar, J., & Varkey, J. (2024). Exploring Epigenetic Modifications in Huntington’s Disease: Implications for Disease Progression and Therapeutic Strategies. Journal of Student Research, 13(4). https://doi.org/10.47611/jsrhs.v13i4.7619

Issue

Section

HS Research Articles