SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis.
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.
['Amador-Arjona|Alejandro|A|', 'Cimadamore|Flavio|F|', 'Huang|Chun-Teng|CT|', 'Wright|Rebecca|R|', 'Lewis|Susan|S|', 'Gage|Fred H|FH|', 'Terskikh|Alexey V|AV|']
D000818:Animals D000831:Animals, Newborn D051792:Basic Helix-Loop-Helix Transcription Factors D015153:Blotting, Western D002453:Cell Cycle D049109:Cell Proliferation D002478:Cells, Cultured D044127:Epigenesis, Genetic D015870:Gene Expression D006624:Hippocampus D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008822:Mice, Transgenic D008856:Microscopy, Fluorescence D009419:Nerve Tissue Proteins D058953:Neural Stem Cells D055495:Neurogenesis D009474:Neurons D018408:Patch-Clamp Techniques D011401:Promoter Regions, Genetic D011485:Protein Binding D034622:RNA Interference D020133:Reverse Transcriptase Polymerase Chain Reaction D055748:SOXB1 Transcription Factors D015533:Transcriptional Activation
SOX2 epigenetics neurogenesis