Sequentially acting SOX proteins orchestrate astrocyte‐ and oligodendrocyte‐specific gene expression

Abstract

SOX transcription factors have important roles during astrocyte and oligodendrocyte development, but how glial genes are specified and activated in a sub-lineage-specific fashion remains unknown. Here, we define glial-specific gene expression in the developing spinal cord using single-cell RNA-sequencing. Moreover, by ChIP-seq analyses we show that these glial gene sets are extensively preselected already in multipotent neural precursor cells through prebinding by SOX3. In the subsequent lineage-restricted glial precursor cells, astrocyte genes become additionally targeted by SOX9 at DNA regions strongly enriched for Nfi binding motifs. Oligodendrocyte genes instead are prebound by SOX9 only, at sites which during oligodendrocyte maturation are targeted by SOX10. Interestingly, reporter gene assays and functional studies in the spinal cord reveal that SOX3 binding represses the synergistic activation of astrocyte genes by SOX9 and NFIA, whereas oligodendrocyte genes are activated in a combinatorial manner by SOX9 and SOX10. These genome-wide studies demonstrate how sequentially expressed SOX proteins act on lineage-specific regulatory DNA elements to coordinate glial gene expression both in a temporal and in a sub-lineage-specific fashion.

Crazy Little Thing Called Sox—New Insights in Oligodendroglial Sox Protein Function

“…A recent study aimed to investigate the effect of Sox9 on oligodendroglial specification and its possible interplay with Sox3 when prebinding regulatory gene regions in NPCs [15]. Single-cell RNA sequencing data from CD133-sorted spinal cord NPCs of E11.5 old mice, as well as from cells isolated from selected regions of the E15.5 mouse spinal cord tissue, were obtained.…”

The SOXE transcription factors—SOX8, SOX9 and SOX10—share a bi-partite transactivation mechanism

“…Transactivation is a focal activity of SOXE proteins. For instance, SOX8 and SOX9 transactivate Sertoli cell-specific genes (15); SOX9 also transactivates chondrocyte-specific genes (16,17); and SOX10 transactivates oligodendrocyte- and melanocyte-specific genes (18,19). A current conundrum is that compelling evidence of redundant and additive activities in multiple processes contrasts with data suggesting that SOXE proteins utilize different transactivation domains.…”

The transcription factor PITX1 drives astrocyte differentiation by regulating the SOX9 gene

“…SOX transcription factors, including SOX9, have important functions during astrocyte and oligodendrocyte development. In glial precursor cells (GPCs), SOX9 function was suppressed under the influence of SOX3, but SOX9 induced astrocyte differentiation when SOX3 was removed (48). SOX9 is known to induce gliogenesis (19) through cooperation with NFIA (20).…”