SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

Abstract

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.SOX2 | neurogenesis | epigenetics C ell fate and differentiation decisions of adult neural progenitor cells (NPCs) are controlled by intrinsic and extrinsic signals from the neurogenic niche (1-3). Recent genomewide analyses of epigenetic regulators in the brain have provided considerable insight into the mechanisms that regulate neural development, neurological disease, and aging (4, 5). The chromatin states of NPCs change dynamically during cell-fate determination and cell differentiation, and chromatin marks such as histone H3 trimethylated Lys 27 (H3K27me3), histone H3 trimethylated Lys 4 (H3K4me3), and histone H3 acetylated Lys 9 (H3K9ac) are essential for regulating the expression of key genes involved in these processes (6). Sex-determining region Y (SRY)-related HMG box 2 (SOX2) is a member of the SOXB1 family of transcription factors, which play important roles in maintaining neural stem/progenitor cell properties, including their capacity to proliferate and self-renew (7,8). In humans, SOX2 mutations are associated with anophthalmia, defective hippocampal development, and seizures (9-11). Most patients with this syndrome experience intellectual disabilities (11), suggesting that loss of SOX2 function affects areas of the brain involved in cognition (e.g., hippocampus). SOX2 deficiency also causes neurodegeneration and impaired neurogenesis in the adult mouse brain (12, 13). However, the molecular mechanisms underlying the function of SOX2 in adult neurogenesis and its role in the human SOX2 anophthalmia syndrome are largely unknown.The subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus is a germinal zone of active neurogenesis during adulthood (14). Indeed, approximately one-third of DG neurons lost during this period are replaced ...

Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea

“…For example, Sox2 loss of function impairs adult neurogenesis and tracheal repair (16,(24)(25)(26). Moreover, Sox2 is upregulated during spinal cord regeneration, with damage inducing the proliferation of Sox2 + cells, and inhibition of Sox2 limiting their regeneration in a dose-dependent manner (27).…”

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

“…Moreover, although RIT1 deficiency permits normal levels of basal neurogenesis, we have previously noted significant defects in hippocampal neurogenesis following traumatic brain injury (28). Sox2-deficient HNPCs display increased cell death during neuronal differentiation (32), and Sox2-null mice have deficits in hippocampal neurogenesis and augmented neurodegeneration (36,37), suggesting that RIT1 may be needed for injury-mediated Sox2 activation. Studies are underway to test this hypothesis.…”

“…2). Because Sox2 has recently been shown to bind to the promoters of poised pro-neural genes in NPCs to enable an appropriate neuronal differentiation (32,35) program, including the neurogenic genes Ngn2 and NeuroD1, we reasoned that RIT1-dependent neurogenic gene expression might rely on Sox2 activation. Indeed, active RIT1 expression both increases Sox2 protein levels (Fig.…”

Opportunities lost and gained: Changes in progenitor competence during nervous system development

“…In this manner, Sox2 prevents the formation of a "closed" H3K27me3 chromatin state, which would otherwise block Wnt-induced expression of neuronal differentiation loci. 50,51 Sox2 conditional knockout mice had lower NeuroD1 levels and apoptosis of young neurons; the latter phenotype could be rescued by targeted re-expression of NeuroD1. 50 The authors propose a model where Sox2 limits PRC2 activity to maintain a poised chromatin state at neuronal differentiation genes, thereby giving them competence to respond to Wnt-induced expression and subsequent neuronal differentiation (Fig.…”