Search

The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 ( SOX9 ) and SOX10 ( SOXE ) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9 Y440X mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9 Y440X causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous Sox9 -null mice are normal. During the ES development of Sox9 Y440X/+ heterozygotes, Sox10 and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. Sox10 heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early Sox9 Y440X/+ mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9 Y440X is implicated in impairing the normal cooperation of SOX9 and SOX10 in repressing the expression of the water channel Aquaporin 3, thereby contributing to endolymphatic hydrops. Our study shows that for a functioning endolymphatic system in the inner ear, SOX9 regulates Sox10 , and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9 Y440X can interfere with the activity of both SOXE factors, exerting effects that can be classified as haploinsufficient/hypomorphic or dominant negative depending on the cell/gene context. This model of disruption of transcription factor partnerships may be applicable to congenital deafness, which affects ∼0.3% of newborns, and other syndromic disorders.

Summary The interaction between tumor and immune system plays a crucial role in both cancer development and treatment response. To facilitate comprehensive investigation of tumor–immune interactions, we have designed a user-friendly web portal TISIDB, which integrated multiple types of data resources in oncoimmunology. First, we manually curated 4176 records from 2530 publications, which reported 988 genes related to anti-tumor immunity. Second, genes associated with the resistance or sensitivity of tumor cells to T cell-mediated killing and immunotherapy were identified by analyzing high-throughput screening and genomic profiling data. Third, associations between any gene and immune features, such as lymphocytes, immunomodulators and chemokines, were pre-calculated for 30 TCGA cancer types. In TISIDB, biologists can cross-check a gene of interest about its role in tumor–immune interactions through literature mining and high-throughput data analysis, and generate testable hypotheses and high quality figures for publication. Availability and implementation http://cis.hku.hk/TISIDB Supplementary information Supplementary data are available at Bioinformatics online.