Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease

Mark T.W. Ebbert, Christian A. Ross, Luc J. Pregent, Rebecca J. Lank, Cheng Zhang, Rebecca B. Katzman, Karen Jansen-West, Yuping Song, Edroaldo Lummertz da Rocha, Carla Palmucci, Pamela Desaro, Amelia E. Robertson, Ana M. Caputo, Dennis W. Dickson, Kevin B. Boylan, Rosa Rademakers, Tamas Ordog, Hu Li, Veronique V. Belzil

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive “multi-omic” analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.

Original languageEnglish (US)
Pages (from-to)715-728
Number of pages14
JournalActa neuropathologica
Volume134
Issue number5
DOIs
StatePublished - Nov 1 2017

Keywords

  • Amyotrophic lateral sclerosis
  • C9orf72
  • DNA methylation
  • Epigenetic modification
  • SERPINA1
  • Transcriptome regulation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease'. Together they form a unique fingerprint.

  • Cite this

    Ebbert, M. T. W., Ross, C. A., Pregent, L. J., Lank, R. J., Zhang, C., Katzman, R. B., Jansen-West, K., Song, Y., da Rocha, E. L., Palmucci, C., Desaro, P., Robertson, A. E., Caputo, A. M., Dickson, D. W., Boylan, K. B., Rademakers, R., Ordog, T., Li, H., & Belzil, V. V. (2017). Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease. Acta neuropathologica, 134(5), 715-728. https://doi.org/10.1007/s00401-017-1760-4