Histone methylation patterns in astrocytes are influenced by age following ischemia

Abstract

In animal models, middle-aged females sustain greater ischemia-induced infarction as compared to adult females. This age difference in infarct severity is associated with reduced functional capacity of astrocytes, a critical neural support cell. The impaired response of astrocytes following stroke in middle-aged females may be related to epigenetic alterations, including histone acetylation or methylation. The present study measured the activity of enzymes that regulate histone acetylation and methylation in cerebral cortical astrocytes of adult (6 month) and middle-aged (11+ month) female rats 48 h following middle cerebral artery occlusion. H3K4 histone methyltransferase activity was decreased in astrocytes from middle-aged females. The next experiment therefore examined H3K4me3 (transcriptional enhancer) and H3K9me3 (transcriptional repressor) in astrocytes from adult and middle-aged females using ChIP-seq analysis. Adult females had more enriched H3K4me3 peaks (304 vs. 26) at transcriptional start sites and fewer H3K9me3 enriched peaks than middle-aged females (4 vs. 22), indicating a pattern of less active chromatin in astrocytes in the older group following ischemia. DAVID clustering analysis of H3K4me3 enriched genes found several functional categories, including cell motility, regulation of apoptosis and the vascular endothelial growth factor (VEGF) pathway. H3K4me3 was enriched at the miR-17-20 cluster and VEGFa, and analysis of a separate set of astrocytes confirmed that VEGF protein expression and miR-20 mRNA expression were significantly greater following ischemia in adult females compared to middle-aged females. These data indicate that astrocytes display less active chromatin with aging and provide new insight into possible mechanisms for differences in stroke severity observed during aging.

The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats

“…Since IGF-1 is a known neuroprotectant for stroke in young and aging animals, we next investigated IGF-1 levels in serum and corticostriatal samples from ischemic and non-ischemic hemispheres Consistent with previous reports [19, 20, 22, 36–38], ET-1 induced MCAo elevated IGF-1 level in ischemic hemisphere in the control (69%) and NaB treated (61%) (Fig. 7a).…”

“…Rats were fed pelleted food (Harlan, Teklad Rodent Diet) and water ad libitum. One week after arrival, animals were subject to daily vaginal smears to determine estrous status as reported previously [19]. Briefly, collected vaginal cells were placed on slides and cell cytology was examined.…”

Inhibition of Histone Methyltransferases SUV39H1 and G9a Leads to Neuroprotection in an in vitro Model of Cerebral Ischemia

“…The more active chromatin in younger rats is associated with higher expression levels of cytoprotective genes. 28 For actual changes in gene transcription, an orchestrated interplay between different epigenetic levels, such as histone methylation and acetylation, is necessary. 9 Both SUV39H1 and G9a act in multiple repressive complexes and interact with regulatory elements to silence transcription.…”

Current Stage and Future Perspective of Stem Cell Therapy in Ischemic Stroke

“…Apart from DNA methylation, ischemia stroke also leads to the dysfunction of some histone modifiers in astrocytes in rat models [57]. Interestingly, as recent studies demonstrated that inhibition of histone methyltransferases SUV39H1 and G9a is able to protection the neurons in the model of cerebral ischemia [58] and these methyltransferases also play a role in the maintenance of DNA methylation [59].…”