Mixed Lineage Leukemia 1 Promoted Neuron Apoptosis in Ischemic Penumbra via Regulating ASK-1/TNF- α Complex

This study aimed to explore the underlying mechanism of neuron apoptosis in ischemic penumbra via histone methyltransferase (HMT) mixed lineage leukemia 1 (MLL1) mediated epigenetic pathway. Mouse IS model was established by middle cerebral artery occlusion (MCAO). Mouse primary cortical mixed cells were cultured and treated with oxygen–glucose deprivation (OGD) to simulate IS process. The expressions of apoptosis signal regulating kinase-1 (ASK-1), pASK-1, cleaved caspase-3, ASK-1/serine–threonine kinase receptor-associated protein (STRAP)/14-3-3 complex, ASK-1/tumor necrosis factor-α (TNF-α) complex, and MLL1 in mouse brain tissue and mouse primary cortical mixed cells were analyzed. The function of MLL1 was investigated using small interfering RNA (siRNA) targeting MLL1 and vector overexpressing MLL1. In vivo inhibition of MLL1 was conducted to explore its value as a therapeutic target. The prognostic value of MLL1 was investigated in IS patients. Results showed that the expressions of ASK-1, pASK-1, cleaved caspase-3, ASK-1/TNF-α complex, and MLL1 increased significantly in ischemic penumbra compared to brain tissue from the control group (P < 0.05). MCAO and OGD significantly upregulated the H3K4me3 level in ASK-1 promoter region and promoted the recruitment of MLL1 to this region (P < 0.05). siMLL1 significantly reversed the proapoptosis effects of OGD in primary cortical mixed cells, while MLL1 overexpression induced apoptosis of cells (P < 0.05). In vi...
Source: Frontiers in Neuroanatomy - Category: Neurology Source Type: research