Insights into the epigenetic mechanisms involving histone lysine methylation and demethylation in ischemia induced damage and repair has therapeutic implication.
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.
Chemical Biology Division, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Uppal Road, Hyderabad 500007, India. Electronic address: sumanachak@iict.res.in.
Sumana
S
Chakravarty
Chemical Biology Division, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Uppal Road, Hyderabad 500007, India.
Priya
P
Jhelum
CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500007, India.
Unis Ahmad
UA
Bhat
CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500007, India.
Wenson D
WD
Rajan
Chemical Biology Division, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Uppal Road, Hyderabad 500007, India.
Swati
S
Maitra
CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500007, India.
Salil S
SS
Pathak
CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500007, India.
Anant B
AB
Patel
CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500007, India. Electronic address: akumar@ccmb.res.in.
Arvind
A
Kumar
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000073398:Demethylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D008239:Lysine / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice
D000600:Amino Acids, Dicarboxylic; D006657:Histones; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine; C040947:oxalylglycine
Cerebral ischemia; Dimethyloxalylglycine (DMOG); Histone lysine demethylases (KDMs); Histone lysine methyl transferases (KMTs); Inflammatory markers; Magnetic resonance imaging (MRI)