Aging, Environment, & DiseaseDNA Methylation and HydroxymethylationHistone Modifications

The Epigenetics of Stroke

princ_rm_photo_of_ct_scan_showing_ischemic_strokeStroke is the 4th leading cause of death in the United States, taking 130,000 lives each year as well as incurring $36.5 billion combined costs of medical expenses and lost productivity. Advanced age is a risk factor for stroke. 66% of patients hospitalized due to stroke are over 65 years old and the prevalence of stroke in people older than 80 is nearly 14%. Additionally, old age also increases the chance of more a severe infarction, poorer survival rates, and less favorable functional recovery [1].

Ischemic stroke accounts for 87% of all strokes. An ischemic stroke occurs when a blood vessel in the brain is occluded, depriving the neural tissue of vital oxygen and glucose. Other forms of strokes include hemorrhagic stroke, which is caused by blood vessel rupture, and transient ischemic attack, which involves a temporary clot in the blood vessel. In order to study ischemic stroke under precise experimental conditions, animal and cell culture models have been established. Previous studies have found that trichostatin-A (TSA), a histone deacetylases inhibitor (HDACI) is protective against cerebral ischemic insults, suggesting  involvement of epigenetic modification in ischemia related neural cell death [2].

Current evidence indicates that epigenetic features of both neurons and astrocytes change during experimentally-induced ischemic conditions [3,4,5]. Prolonged oxygen and glucose deprivation (OGD) in cultured primary neurons has been shown to result in dramatic reduction of acetylation of histone H3 and H4 [3,5]. This reduction is caused by a sustained activity of histone deacetylases, and renders neurons vulnerable to ischemic injury. TSA reverses the loss of histone acetylation via PI3K/Akt pathway, exerting neuroprotective effects following ischemia [2]. In cultured astrocytes, OGD is reported to double the global DNA methylation levels [4]. Notably, despite global hypermethylation, two important genes in the beta-amyloid processing pathway, APP and BACE1, showed hypomethylation, consistent with the elevated risk of developing Alzheimer’s disease among stroke patients [4]. OGD is also accompanied by decreased acetylation of histone H3 and H4. Interestingly, inhibiting the JNK signaling pathway prior to OGD was effective in normalizing global DNA methylation and histone acetylation levels [4]. Therefore, the JNK pathway could be a promising target for stroke therapeutics.

In middle-aged female rats, focal ischemia causes larger infarction than in younger adult female rats [6]. This increase in ischemic severity is believed to be the result of impaired astrocyte function in the aging brain. Astrocytes are able to partially mitigate the detrimental effects of ischemia, but unfortunately, this capacity decreases during aging.  Astrocytes from middle age rats are less effective at clearing cytotoxic molecules such as glutamate and produce more pro-inflammatory cytokines[7].

It has also been demonstrated that Astrocytes from middle-aged female rats (12mo) undergoing experimentally-induced ischemia, have less H3K4 histone methyltransferase activity than astrocytes from young-adult (6mo) female rats [8]. Astrocytes from middle-aged rats were enriched with H3K9me3, a transcriptional repressor mark, and possessed less of the transcriptional enhancer H3K4me3 [8]. Therefore, astrocytes from older female rats are less transcriptionally active following ischemic insult. Considering the loss of histone acetylation in both neurons and astrocytes, the global DNA hypermethylaton in astrocytes under ischemic conditions, and the neuroprotective effect of TSA,  it is reasonable to conclude that repressed transcriptional activity in neural cells following glucose and oxygen deprivation is detrimental to cell survival. Additionally, age-related decreases in transcription in astrocytes from older animals may therefore partially explain the greater ischemia severity seen in human elderly patients. It is imperative to profile the epigenetic features of astrocytes from older animals and patients in greater detail, in order to understand how they respond to global epigenetic manipulations under normal and ischemic conditions, in hope of improving prognosis in elderly ischemic patients.

1. Sohrabji F, Bake S, & Lewis DK (2013). Age-related changes in brain support cells: Implications for stroke severity. Neurochemistry international, 63 (4), 291-301 PMID: 23811611

2. Ma XH, Gao Q, Jia Z, & Zhang ZW (2015). Neuroprotective capabilities of TSA against cerebral ischemia/reperfusion injury via PI3K/Akt signaling pathway in rats. The International journal of neuroscience, 125 (2), 140-6 PMID: 24730998

3. Dmitriev RI, & Papkovsky DB (2015). In vitro ischemia decreases histone H4K16 acetylation in neural cells. FEBS letters, 589 (1), 138-44 PMID: 25479088

4. Yang Q, Wu X, Sun J, Cui J, & Li L (2014). Epigenetic Features Induced by Ischemia-Hypoxia in Cultured Rat Astrocytes. Molecular neurobiology PMID: 25465244

5. Yildirim F, Ji S, Kronenberg G, Barco A, Olivares R, Benito E, Dirnagl U, Gertz K, Endres M, Harms C, & Meisel A (2014). Histone acetylation and CREB binding protein are required for neuronal resistance against ischemic injury. PloS one, 9 (4) PMID: 24748101

6. Selvamani A, & Sohrabji F (2010). Reproductive age modulates the impact of focal ischemia on the forebrain as well as the effects of estrogen treatment in female rats. Neurobiology of aging, 31 (9), 1618-28 PMID: 18829137

7. Lewis DK, Thomas KT, Selvamani A, & Sohrabji F (2012). Age-related severity of focal ischemia in female rats is associated with impaired astrocyte function. Neurobiology of aging, 33 (6), 11230-16 PMID: 22154819

8. Chisholm N, Henderson M, Selvamani A, Park MJ, Dindot S, Miranda R, & Sohrabji F (2015). Histone Methylation Patterns in Astrocytes are Influenced by Age Following Ischemia. Epigenetics : official journal of the DNA Methylation Society PMID: 25565250

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Muye Zhu

Muye Zhu

Muye is pursuing a PhD of Neuroscience at USC where she is "constructing a map of the complex neural circuits in rodent brain to shine light on the building blocks of our neurological functions: senses, thoughts, memory, urges, etc." Apart from that, Muye enjoys food, reading, good jokes, rock climbing and many other finer things in life.