Insights into the epigenetic mechanisms involving histone lysine methylation and demethylation in ischemia induced damage and repair has therapeutic implication

Sumana Chakravarty, Priya Jhelum, Unis Ahmad Bhat, Wenson D. Rajan, Swati Maitra, Salil S. Pathak, Anant B. Patel, Arvind Kumar

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Cerebral ischemic stroke is one of the leading causes of death and disability worldwide. Therapeutic interventions to minimize ischemia-induced neural damage are limited due to poor understanding of molecular mechanisms mediating complex pathophysiology in stroke. Recently, epigenetic mechanisms mostly histone lysine (K) acetylation and deacetylation have been implicated in ischemic brain damage and have expanded the dimensions of potential therapeutic intervention to the systemic/local administration of histone deacetylase inhibitors. However, the role of other epigenetic mechanisms such as histone lysine methylation and demethylation in stroke-induced damage and subsequent recovery process is elusive. Here, we established an Internal Carotid Artery Occlusion (ICAO) model in CD1 mouse that resulted in mild to moderate level of ischemic damage to the striatum, as suggested by magnetic resonance imaging (MRI), TUNEL and histopathological staining along with an evaluation of neurological deficit score (NDS), grip strength and rotarod performance. The molecular investigations show dysregulation of a number of histone lysine methylases (KMTs) and few of histone lysine demethylases (KDMs) post-ICAO with significant global attenuation in the transcriptionally repressive epigenetic mark H3K9me2 in the striatum. Administration of Dimethyloxalylglycine (DMOG), an inhibitor of KDM4 or JMJD2 class of histone lysine demethylases, significantly ameliorated stroke-induced NDS by restoring perturbed H3K9me2 levels in the ischemia-affected striatum. Overall, these results highlight the novel role of epigenetic regulatory mechanisms controlling the epigenetic mark H3K9me2 in mediating the stroke-induced striatal damage and subsequent repair following mild to moderate cerebral ischemia.

Original languageEnglish (US)
Pages (from-to)152-164
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1863
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 Elsevier B.V.

Keywords

  • Cerebral ischemia
  • Dimethyloxalylglycine (DMOG)
  • Histone lysine demethylases (KDMs)
  • Histone lysine methyl transferases (KMTs)
  • Inflammatory markers
  • Magnetic resonance imaging (MRI)

Fingerprint

Dive into the research topics of 'Insights into the epigenetic mechanisms involving histone lysine methylation and demethylation in ischemia induced damage and repair has therapeutic implication'. Together they form a unique fingerprint.

Cite this