Abstract
Estrogens are neuroprotective factors in several neurological diseases. Neuroglobin (NGB) is one of the estrogen target genes involved in neuroprotection, but little is known about its transcriptional regulation. Estrogen genomic pathway in gene expression regulation is mediated by estrogen receptors (ERα and ERβ) that bind to specific regulatory genomic regions. We focused our attention on 17β-estradiol (E2)-induced NGB expression in human differentiated neuronal cell lines (SK-N-BE and NT-2). Previously, using bioinformatics analysis we identified a putative enhancer in the first intron of NGB locus. Therefore, we observed that E2 increased the enrichment of the H3K4me3 epigenetic marks at the promoter and of the H3K4me1 and H3K27Ac at the intron enhancer. In these NGB regulatory regions, we found estrogen receptor alpha (ERα) binding suggesting that ERα may mediate chromatin remodeling to induce NGB expression upon E2 treatment. Altogether our data show that NGB expression is regulated by ERα binding on genomic regulatory regions supporting hormone therapy applications for the neuroprotection against neurodegenerative diseases.
Highlights
17β-estradiol (E2) has neuroprotective activity in several models of neurodegenerative disorders, such as multiple sclerosis, ischemia, stroke and Alzheimer’s disease (AD; Arevalo et al, 2015)
These are well assessed data, the question whether ERα may exert a direct effect on NGB transcription has not been worked out in detail, we addressed this question in the present work using SK-N-BE and NT-2 differentiated cells as neuronal-like in vitro models
E2-induced NGB protein expression in neuroblastoma cell lines, SK-N-BE, has been previously demonstrated (De Marinis et al, 2011) and, here we investigated SK-N-BE and NT2 cells upon conditions leading to cell differentiation
Summary
17β-estradiol (E2) has neuroprotective activity in several models of neurodegenerative disorders, such as multiple sclerosis, ischemia, stroke and Alzheimer’s disease (AD; Arevalo et al, 2015). E2 increases NGB levels in a dose-dependent manner (1–10 nM) This effect is reached in 1 h treatment and is maintained for 24 h in human neuroblastoma cell lines and in mouse primary hippocampal neurons. ERβ signaling is mediated by membrane-associated proteins and has an effect on mitochondria as apoptosis protection (De Marinis et al, 2011, 2013b; Fiocchetti et al, 2014, 2015) These are well assessed data, the question whether ERα may exert a direct effect on NGB transcription has not been worked out in detail, we addressed this question in the present work using SK-N-BE and NT-2 differentiated cells as neuronal-like in vitro models. The comparison of two cell lines from different origin (SK-N-BE, human neuroblastoma cell lines, and NT-2, human embryonal carcinoma cell line) upon differentiation conditions represented models to study E2-induced NGB transcription regulation and find genomic regulatory regions
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