Sequentially acting Sox transcription factors in neural lineage development

Abstract

Pluripotent embryonic stem (ES) cells can generate all cell types, but how cell lineages are initially specified and maintained during development remains largely unknown. Different classes of Sox transcription factors are expressed during neurogenesis and have been assigned important roles from early lineage specification to neuronal differentiation. Here we characterize the genome-wide binding for Sox2, Sox3, and Sox11, which have vital functions in ES cells, neural precursor cells (NPCs), and maturing neurons, respectively. The data demonstrate that Sox factor binding depends on developmental stage-specific constraints and reveal a remarkable sequential binding of Sox proteins to a common set of neural genes. Interestingly, in ES cells, Sox2 preselects for neural lineagespecific genes destined to be bound and activated by Sox3 in NPCs. In NPCs, Sox3 binds genes that are later bound and activated by Sox11 in differentiating neurons. Genes prebound by Sox proteins are associated with a bivalent chromatin signature, which is resolved into a permissive monovalent state upon binding of activating Sox factors. These data indicate that a single key transcription factor family acts sequentially to coordinate neural gene expression from the early lineage specification in pluripotent cells to later stages of neuronal development.

A direct fate exclusion mechanism by Sonic hedgehog-regulated transcriptional repressors

“…3A,B). SoxB1 transcription factors (Sox1, 2 and 3) play key roles in the active maintenance and fate determination of neural progenitors (Bergsland et al, 2011;Bylund et al, 2003;Graham et al, 2003;Oosterveen et al, 2012;Peterson et al, 2012). Examination of the Nkx2.2, Nkx6.1 and Olig2 datasets showed a consistent enrichment of a Sox motif in bound regions (Fig.…”

“…4A). Similarly, Sox3 DNA target interactions in neural progenitors (Bergsland et al, 2011) showed an extensive overlap with the repressor trio (46%) (supplementary material Fig. S6B).…”

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

“…Previous ChIP-seq studies have found that SOX2 is bound to hundreds of known or presumably poised loci that are transcriptionally inactive but will be expressed during differentiation (26,38); however, its biological role at these genes was unknown. It is widely accepted that bivalent domains are central to maintaining genes in a poised state, ensuring proper and robust responses to differentiation cues (57).…”

“…In NPCs, the chromatin regions of proneural and neurogenic genes contain high levels of both H3K27me3 and H3K4me3 (37,38); such bivalent marks maintain the genes transcriptionally silent but poised for activation once differentiation cues are received (32). To understand the regulatory function of SOX2 in activation of the neurogenic program, we examined previously published ChIP-sequencing (ChIP-seq) data including the occurrence of H3K27me3 and H3K4me3 marks at SOX2-binding sites in mouse ES cell-derived NPCs (6,26).…”

Plasticity of DNA methylation in a nerve injury model of pain

“…26 Hypermethylated alive deserts were enriched for SOX gene family (P < 10 ¡51 ) and neurofibromin 1 (NF1) binding sites (P < 10 ¡22 ). SOX genes are involved in neuronal development 27 and axon regeneration 28 and NF1 has long been recognized for its critical role in the PNS.…”