Abstract
During neuronal development, β-actin serves an important role in growth cone mediated axon guidance. Consistent with this notion, in vivo ablation of the β-actin gene leads to abnormalities in the nervous system. However, whether β-actin is involved in the regulation of neuronal gene programs is not known. In this study, we directly reprogramed β-actin+/+ WT, β-actin+/- HET and β-actin-/- KO mouse embryonic fibroblast (MEFs) into chemically induced neurons (CiNeurons). Using RNA-seq analysis, we profiled the transcriptome changes among the CiNeurons. We discovered that induction of neuronal gene programs was impaired in KO CiNeurons in comparison to WT ones, whereas HET CiNeurons showed an intermediate levels of induction. ChIP-seq analysis of heterochromatin markers demonstrated that the impaired expression of neuronal gene programs correlated with the elevated H3K9 and H3K27 methylation levels at gene loci in β-actin deficient MEFs, which is linked to the loss of chromatin association of the BAF complex ATPase subunit Brg1. Together, our study shows that heterochromatin alteration in β-actin null MEFs impedes the induction of neuronal gene programs during direct reprograming. These findings are in line with the notion that H3K9Me3-based heterochromatin forms a major epigenetic barrier during cell fate change.
Highlights
In mammals, six functional actin genes expressed in a tissue-specific manner form the actin cytoskeleton, a basic physical and organizational intracellular structure that dynamically regulates cell polarity, membrane properties and cell behavior [1, 2]
December 17, 2018 β-actin in heterochromatin maintenance during neurogenesis of neuronal program expression, suggesting that β-actin dosage plays an important role during direct neuronal reprograming
Together our study demonstrates that β-actin is required for the optimal induction of neuronal gene programs during direct reprograming by presetting a favorable chromatin status
Summary
Six functional actin genes expressed in a tissue-specific manner form the actin cytoskeleton, a basic physical and organizational intracellular structure that dynamically regulates cell polarity, membrane properties and cell behavior [1, 2]. Actin-containing structures are involved in neuronal development, such as growth cone dynamics, dendritic spines remodeling and neuronal precursor migration [3,4,5]. Β- and γ-actin are the two actin isoforms expressed in mammalian neurons, but they show different localization and dynamics during neuronal development [6, 7]. Γ-actin seems to be evenly present in cell body, dendrites and axons, while βactin is confined to structures undergoing remodeling such as the growth cone [7, 8]. Whether the localized sorting of β-actin mRNA is essential for in vivo neuronal development remains controversial. Motor-neuron specific β-actin knock-out mice show no observable defects in axonal regeneration [11]
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