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Uncovering Sex-Specific Epigenetic Regulatory Mechanism Involving H3k9me2 in Neural Inflammation, Damage, and Recovery in the Internal Carotid Artery Occlusion Mouse Model

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Abstract

Cerebral ischemic stroke is one of the foremost global causes of death and disability. Due to inadequate knowledge in its sequential disease mechanisms, therapeutic efforts to mitigate acute ischemia-induced brain injury are limited. Recent studies have implicated epigenetic mechanisms, mostly histone lysine acetylation/deacetylation, in ischemia-induced neural damage and death. However, the role of lysine methylation/demethylation, another prevalent epigenetic mechanism in cerebral ischemia has not undergone comprehensive investigation, except a few recent reports, including those from our research cohort. Considering the impact of sex on post-stroke outcomes, we studied both male and female mice to elucidate molecular details using our recently developed Internal Carotid Artery Occlusion (ICAO) model, which induces mild to moderate cerebral ischemia, primarily affecting the striatum and ventral hippocampus. Here, we demonstrate for the first time that female mice exhibit faster recovery than male mice following ICAO, evaluated through neurological deficit score and motor coordination assessment. Furthermore, our investigation unveiled that dysregulated histone lysine demethylases (KDMs), particularly kdm4b/jmjd2b are responsible for the sex-specific variance in the modulation of inflammatory genes. Building upon our prior reportage blocking KDMs by DMOG (Dimethyloxalylglycine) and thus preventing the attenuation in H3k9me2 reduced the post-ICAO transcript levels of the inflammatory molecules and neural damage, our present study delved into investigating the differential role of H3k9me2 in the regulation of pro-inflammatory genes in female vis-à-vis male mice underlying ICAO-induced neural damage and recovery. Overall, our results reveal the important role of epigenetic mark H3k9me2 in mediating sex-specific sequential events in inflammatory response, elicited post-ICAO.

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The data that support the findings are available with the corresponding author, may be available on reasonable request.

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Acknowledgements

This research was initiated by the Council of Scientific and Industrial Research (CSIR), India network projects [(BSC0103-UNDO) to SC and AK] and later supported by ICMR grant [5/4-5/3/17/Neuro/2022-NCD-1 to SC]. MR, VV, PBT, SP and KS wish to acknowledge CSIR India, Department of Biotechnology (DBT) and DST-INSPIRE for their doctoral fellowships, respectively. In addition, the authors would like to specially acknowledge B. Jyothilakshmi of the Centre for Cellular and Molecular Biology (CCMB), Hyderabad, for the maintenance and care of animals throughout the study period. KIM Department of CSIR-IICT is greatly acknowledged for generating institutional publication number IICT/Pubs/2023/186.

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  1. Applied Biology, CSIR- Indian Institute of Chemical Technology (IICT), Tarnaka, Hyderabad, 500007, India

    Mydhili Radhakrishnan, Vincy Vijay, Papia Basuthakur, Shashikant Patel, Kalyani Soren & Sumana Chakravarty

  2. Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India

    B. Supraja Acharya & Arvind Kumar

  3. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India

    Mydhili Radhakrishnan, Vincy Vijay, Papia Basuthakur, Shashikant Patel, Kalyani Soren, Arvind Kumar & Sumana Chakravarty

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SC and AK conceived the study. SC and AK designed and supervised all the experiments. The experiments performed by MR, VV, SA, PB, SP, KS, and SC, SC and AK arranged the resources and analyzed the results. MR, SC, and AK. wrote the original draft of the manuscript and made the edits to make the final version. All authors reviewed and edited the manuscript for their part.

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Radhakrishnan, M., Vijay, V., Supraja Acharya, B. et al. Uncovering Sex-Specific Epigenetic Regulatory Mechanism Involving H3k9me2 in Neural Inflammation, Damage, and Recovery in the Internal Carotid Artery Occlusion Mouse Model. Neuromol Med 26, 3 (2024). https://doi.org/10.1007/s12017-023-08768-9

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