A far-upstream (−70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration

Abstract

SOX9 encodes a transcription factor that presides over the specification and differentiation of numerous progenitor and differentiated cell types, and although SOX9 haploinsufficiency and overexpression cause severe diseases in humans, including campomelic dysplasia, sex reversal and cancer, the mechanisms underlying SOX9 transcription remain largely unsolved. We identify here an evolutionarily conserved enhancer located 70-kb upstream of mouse Sox9 and call it SOM because it specifically activates a Sox9 promoter reporter in most Sox9-expressing somatic tissues in transgenic mice. Moreover, SOM-null fetuses and pups reduce Sox9 expression by 18–37% in the pancreas, lung, kidney, salivary gland, gut and liver. Weanlings exhibit half-size pancreatic islets and underproduce insulin and glucagon, and adults slowly recover from acute pancreatitis due to a 2-fold impairment in Sox9 upregulation. Molecular and genetic experiments reveal that Sox9 protein dimers bind to multiple recognition sites in the SOM sequence and are thereby both necessary and sufficient for enhancer activity. These findings thus uncover that Sox9 directly enhances its functions in somatic tissue development and adult regeneration through SOM-mediated positive auto-regulation. They provide thereby novel insights on molecular mechanisms controlling developmental and disease processes and suggest new strategies to improve disease treatments.

Transcription Factor SOX9 Plays a Key Role in the Regulation of Visual Cycle Gene Expression in the Retinal Pigment Epithelium

“…First, we did not observe decreased Sox9 expression in heterozygous Sox9 cko/ϩ mice. Because cre-mediated recombination clearly occurred, this suggests compensatory up-regulation from the remaining wild-type Sox9 allele and could indicate the existence of robust autoregulation and/or feed-forward loops for SOX9 to maintain its level in RPE cells, as has been described in other tissues (68,69). Secondly, mouse Best1 expression was not down-regulated in Sox9 cko mice, whereas human BEST1 is a target of SOX9.…”

Establishing neural crest identity: a gene regulatory recipe

“…That FoxD3 acts as a direct regulator of Sox10 in migratory cells is supported by another study that identified an intronic enhancer in the zebrafish sox10 locus, which contains FoxD3, Sox and LEF/TCF binding sites (Dutton et al, 2008). Sox9, another SoxE gene that is maintained throughout neural crest migration, has also been shown to directly activate its own transcription through a distant upstream enhancer in the mouse (Mead et al, 2013). Thus, positive self-regulation is a common feature of genes that are continuously expressed by the migratory neural crest.…”

Transcription factors related to chondrogenesis in pleomorphic adenoma of the salivary gland: a mechanism of mesenchymal tissue formation

“…11 This trio of transcription factors can induce chondrocyte differentiation in both chondrogenic mesenchymal cells and nonchondrogenic cells already committed to other lineages, including epithelial cells derived from the cervix, liver, and kidney. 10 Mouse salivary gland cells have been shown to express Sox9, 24 as do human salivary gland cells. Both duct and acinar cells expressed Sox9.…”

“…Recently, mouse salivary gland cells, the cells of origin of pleomorphic adenoma, were found to express Sox9. 24 However, expression of Sox proteins in human salivary gland and pleomorphic adenoma is unknown as far as we know. In the present study, we investigated the expression of positive and negative transcriptional regulators of chondrogenesis in pleomorphic adenoma and salivary gland tissues, and cell lines.…”