SOX transcription factors : multifaceted regulators of central nervous system development

The central nervous system (CNS) is composed of three major cell types, namely neurons, astrocytes and oligodendrocytes that are mainly generated during embryonic stages by multipotent neural progenitor cells (NPCs). The decision of a NPC to remain in a self-renewing, undifferentiated state, or to commit to neuronal or glial differentiation is guided by the combined actions of transcription factors on their downstream target genes. SOX transcription factors have been shown to have key roles during neural lineage formation. In this thesis, we used several next-generation sequencing approaches to study the molecular mechanisms by which SOX transcription factors regulate the maintenance and differentiation of NPCs during early neuronal and glial lineage development.

In Paper I, we investigated how SOX2, SOX3 and SOX11 proteins achieve their distinct functions during neuronal lineage development by characterizing their genome-wide binding profiles in embryonic stem cells (ESCs), NPCs and neurons. We propose a model of sequentially acting SOX proteins during neural lineage formation, whereby SOX proteins prebind large sets of poised silent genes in ESCs and NPCs that are subsequently activated by alternative SOX proteins at later stages of neuronal differentiation.

In Paper II, we examined how chromatin accessibility and transcription factor binding interact to regulate the establishment of different gene expression profiles in NPCs originating from the developing mouse cortex and spinal cord. We found that despite being ubiquitously expressed in all NPCs of the developing CNS, SOX2 regulates the establishment of spatially distinct gene expression programs by interacting with region-specific partner factors on a permissive chromatin landscape.

In Paper III, we characterized the genome-wide binding profile of SOX3 in SOX9 in glial progenitor cells in order to determine their regulatory roles during the development of astrocytes and oligodendrocytes. We show that glial gene expression, similar to neuronal gene expression, is regulated by sequentially acting pre-binding SOX proteins.

Altogether, the results presented in this thesis provide new molecular insights into the mechanisms by which SOX proteins achieve their distinct functional roles during neuronal and glial lineage development.

List of scientific papers

I. Maria Bergsland, Daniel Ramsköld, Cécile Zaouter, Susanne Klum, Rickard Sandberg and Jonas Muhr. (2011). Sequentially acting Sox transcription factors in neural lineage development. Genes & Development. 25, 2453-64.
https://doi.org/10.1101/gad.176008.111

II. Daniel W. Hagey, Cécile Zaouter, Gaëlle Combeau, Monika Andersson Lendahl, Olov Andersson, Mikael Huss and Jonas Muhr. (2016). Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells. Genome Research. 26, 908-17.
https://doi.org/10.1101/gr.203513.115

III. Cécile Zaouter, Susanne Klum, Zjanna Alekseenko, Åsa K. Bjöklund, Daniel W. Hagey, Johan Ericson, Jonas Muhr and Maria Bergsland. scRNA-seq and ChIP-seq analyses in glial progenitors reveal extensive SOX9 pre-binding to astrocyte and oligodendrocyte specific genes. [Manuscript]