Abstract
Neural stem/progenitor cells (NSPCs) persist in the mammalian brain throughout life and can be activated in response to the physiological and pathophysiological stimuli. Epigenetic reprogramming of NPSC represents a novel strategy for enhancing the intrinsic potential of the brain to regenerate after brain injury. Therefore, defining the epigenetic features of NSPCs is important for developing epigenetic therapies for targeted reprogramming of NSPCs to rescue neurologic function after injury. In this study, we aimed at defining different subtypes of NSPCs by individual histone methylations. We found the three histone marks, histone H3 lysine 4 trimethylation (H3K4me3), histone H3 lysine 27 trimethylation (H3K27me3), and histone H3 lysine 36 trimethylation (H3K36me3), to nicely and dynamically portray individual cell types during neurodevelopment. First, we found all three marks co-stained with NSPC marker SOX2 in mouse subventricular zone. Then, CD133, Id1, Mash1, and DCX immunostaining were used to define NSPC subtypes. Type E/B, B/C, and C/A cells showed high levels of H3K27me3, H3K36me3, and H3K4me3, respectively. Our results reveal defined histone methylations of NSPC subtypes supporting that epigenetic regulation is critical for neurogenesis and for maintaining NSPCs.
Highlights
In the postnatal mammalian brain, most of the neural stem/progenitor cells (NSPCs) are spatially restricted to two specific brain regions: the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone (SVZ)Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Histone modifications are post-translational modifications to histone proteins which include methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation
C57BL/6N mouse strain was used for this research and all mouse experiments were approved by the Animal Research Committee and the Norwegian Food Safety Authority (NFDA), and conducted in accordance with the rules and regulations of the Federation of European Laboratory Animal Science Associations (FELASA)
Just 4% of PCNA-positive cells co-stained with H3K27me3 compared with 70% for H3K36me3 and 75% for H3K4me3 (Fig. 6c, d). These results strongly indicate that high levels of H3K36me3 and H3K4em3 correlate very well with proliferating cells in SVZ at early postnatal neurodevelopment
Summary
Histone modifications are post-translational modifications to histone proteins which include methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation. These modifications have biological roles and can be inherited and are referred to as epigenetic marks. Specific histone methylation marks at promoter regions affect transcription activities [5]. Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 36 trimethylation (H3K36me3) are associated with active promoters and gene bodies of actively transcribed genes. This results in increased transcription activity, whereas histone H3 lysine 27 trimethylation (H3K27me3) is linked to transcriptional
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