Abstract
Sox3/SOX3 is one of the earliest neural markers in vertebrates. Together with the Sox1/SOX1 and Sox2/SOX2 genes it is implicated in the regulation of stem cell identity. In the present study, we performed the first analysis of epigenetic mechanisms (DNA methylation and histone marks) involved in the regulation of the human SOX3 gene expression during RA-induced neural differentiation of NT2/D1 cells. We show that the promoter of the human SOX3 gene is extremely hypomethylated both in undifferentiated NT2/D1 cells and during the early phases of RA-induced neural differentiation. By employing chromatin immunoprecipitation, we analyze several histone modifications across different regions of the SOX3 gene and their dynamics following initiation of differentiation. In the same timeframe we investigate profiles of selected histone marks on the promoters of human SOX1 and SOX2 genes. We demonstrate differences in histone signatures of SOX1, SOX2 and SOX3 genes. Considering the importance of SOXB1 genes in the process of neural differentiation, the present study contributes to a better understanding of epigenetic mechanisms implicated in the regulation of pluripotency maintenance and commitment towards the neural lineage.
Highlights
SOX3/Sox3 is an X-linked member of SOXB1 (SOX1-3) subfamily of transcriptional regulators [1,2,3]
Due to their similarity with human embryonal stem cells (hESCs) and the property to differentiate into morphologically and physiologically mature neurons after exposure to retinoic acid (RA), NT2/D1 cells represent an appropriate in vitro model to study the process of human neural differentiation [24,28,29]
In our previous studies and reports made by other groups, NT2/D1 cell line was used for the analyses of human SOX genes expression and regulation [12,13,14,15,17,23,32,33,34,35,36,37]
Summary
SOX3/Sox is an X-linked member of SOXB1 (SOX1-3) subfamily of transcriptional regulators [1,2,3]. Together with SOX1 and SOX2 it is expressed in neural progenitors where they counteract the activity of proneural proteins and maintain undifferentiated state of progenitor cells [4]. SOX2 gene, the closest relative of SOX3, is one of the core pluripotency factors involved in the regulation of stemness and differentiation [3,5,6]. SOX3 is recognized as one of the earliest neural markers in vertebrates; up to date the role of Sox in neural development has been the most studied aspect of the Sox action.
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