期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：15
页码：E1936-E1945
DOI：10.1073/pnas.1421480112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSex-determining region Y-related HMG box 2 (SOX2) is a well-established marker of neural stem and progenitor cells, and its function was shown to be required for the self-renewal of these cells. However, the function of SOX2 in neuronal differentiation is poorly understood. Here we described a novel role of SOX2 in neuronal differentiation in which SOX2 binds to bivalently marked promoters of poised proneural genes in neural progenitor cells and limits the activity of polycomb repressive complex 2 and excessive levels of histone H3 Lys 27 trimethylation. We propose a novel function of SOX2 in maintaining a permissive epigenetic state thus enabling proper activation of the neuronal differentiation program under neurogenic cue. Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.
