The Sox Family of Transcription Factors: Versatile Regulators of Stem and Progenitor Cell Fate
ABSTRACT Sox family transcription factors are well-established regulators of cell fate decisions during development. Accumulating evidence documents that they play additional roles in adult tissue homeostasis and regeneration. Remarkably, forced expression of Sox factors, in combination with other synergistic factors, reprograms differentiated cells into somatic or pluripotent stem cells. Dysregulation of Sox factors has been further implicated in diseases including cancer. Here, we review molecular and functional evidence linking Sox proteins with stem cell biology, cellular reprogramming, and disease with an emphasis on Sox2.
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ABSTRACT: Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.Cell Stem Cell 01/2015; 16(1). DOI:10.1016/j.stem.2014.10.019 · 22.15 Impact Factor
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ABSTRACT: Hair follicle-derived neural crest stem cells can be induced to differentiate into Schwann cells in vivo and in vitro. However, the underlying regulatory mechanism during cell differentiation remains poorly understood. This study isolated neural crest stem cells from human hair follicles and induced them to differentiate into Schwann cells. Quantitative RT-PCR showed that microRNA (miR)-21 expression was gradually increased during the differentiation of neural crest stem cells into Schwann cells. After transfection with the miR-21 agonist (agomir-21), the differentiation capacity of neural crest stem cells was enhanced. By contrast, after transfection with the miR-21 antagonist (antagomir-21), the differentiation capacity was attenuated. Further study results showed that SOX-2 was an effective target of miR-21. Without compromising SOX2 mRNA expression, miR-21 can down-regulate SOX protein expression by binding to the 3'-UTR of miR-21 mRNA. Knocking out the SOX2 gene from the neural crest stem cells significantly reversed the antagomir-21 inhibition of neural crest stem cells differentiating into Schwann cells. The results suggest that miR-21 expression was increased during the differentiation of neural crest stem cells into Schwann cells and miR-21 promoted the differentiation through down-regulating SOX protein expression by binding to the 3'-UTR of SOX2 mRNA.Neural Regeneration Research 04/2014; 9(8):828-36. DOI:10.4103/1673-5374.131599 · 0.23 Impact Factor
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ABSTRACT: Teleost fish underwent whole genome duplication around 450 million years ago followed by diploidisation and loss of 80-85% of the duplicated genes. To identify a deep signature of this teleost-specific whole genome duplication (TSGD) we searched for duplicated genes that were systematically and uniquely retained in one or other of the super-orders Ostariophysi and Acanthopterygii. TSGD paralogues comprised 17-21% of total gene content. Some 2.6% (510) of TSGD paralogues were present as pairs in the Ostariophysi genomes of Danio rerio (Cypriniformes) and Astyanax mexicanus (Characiformes), but not in species from 4 orders of Acanthopterygii (Gasterosteiformes, Gasterosteus aculeatus; Tetraodontiformes, Tetraodon nigroviridis; Perciformes, Oreochromis niloticus and Beloniformes, Oryzias latipes) where a single copy was identified. Similarly, 1.3% (418) of total gene number represented cases where TSGD paralogues pairs were systematically retained in the Acanthopterygian, but conserved as a single copy in Ostariophysi genomes. We confirmed the generality of these results by phylogenetic and synteny analysis of 40 randomly selected linage specific TSGD paralogues (LSPs) completed with the transcriptomes of three additional Ostariophysi species (Ictalurus punctatus (Siluriformes), Synocyclocheilus species (Cypriniformes) and Piaractus mesopotamicus (Characiformes)). No chromosome bias was detected in TSGD paralogue retention. Gene ontology (GO) analysis revealed significant enrichment of GO terms relative to the human GO SLIM database for "growth", "Cell differentiation" and "Embryo development" in Ostariophysi and for "Transport", "Signal Transduction" and "Vesicle mediated transport" in Acanthopterygii. The observed patterns of paralogue retention are consistent with different diploidisation outcomes having contributed to the evolution/diversification of each super-order.Genome Biology and Evolution 04/2014; DOI:10.1093/gbe/evu074 · 4.53 Impact Factor