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

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.

Evidence for independent domestication of sheep mtDNA lineage A in India and introduction of lineage B through Arabian sea route.

India ranks the second in the world in terms of its sheep population with approximately 74.26 million represented by 44 well-described breeds in addition to several non-descript populations. Genetic diversity and phylogeography of Indian sheep breeds remain poorly understood, particularly for south Indian breeds. To have a comprehensive view of the domestication history of Indian sheep, we sequenced the mitochondrial DNA (mtDNA) control region (D-loop) and cytochrome b gene (CYTB) of 16 Indian domestic sheep breeds, most of them (13) from the south India. We analysed these sequences along with published data of domestic and wild sheep from different countries, including India. The haplotype diversity was relatively high in Indian sheep, which were classified into the three known mtDNA lineages, namely A, B and C. Lineage A was predominant among Indian sheep whereas lineages B and C were observed at low frequencies but C was restricted to the breeds of north and east India. The median joining network showed five major expanding haplogroups of lineage A (A1-A5). Out of which, A2, A4 and A5 were more frequent in Indian sheep in contrast to breeds from other parts of the world. Among the 27 Indian sheep breeds analysed, Mandya and Sonadi breeds were significantly different from other Indian breeds in the MDS analyses. This was explained by a very high contribution of lineage B into these two breeds. The Approximate Bayesian Computation (ABC) provided evidence for the domestication of lineage A sheep in the Indian subcontinent. Contrary to the current knowledge, we also found strong support for the introduction of lineage B into Indian subcontinent through sea route rather than from the Mongolian Plateau. The neighbour-joining tree of domestic and wild sheep revealed the close genetic relationship of Indian domestic sheep with Pakistani wild sheep O. vignei blanfordi. Based on our analyses and archaeological evidences, we suggest the Indian subcontinent as one of the domestication centres of the lineage A sheep, while lineage B sheep might have arrived into India from elsewhere via Arabian sea route. To the best of our knowledge, this is the first comprehensive study on Indian sheep where we have analysed more than 740 animals belonging to 27 sheep breeds raised in various regions of India. Our study provides insight into the understanding of the origin and migratory history of Indian sheep.