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Reprogramming scleroderma-specific and normal fibroblast gene subsets using single versus multiple transcription factors

  • Author(s): Van Buren, Tyler Martin
  • et al.
Abstract

The recent successes of reprogramming iPS cells and other cell types offer a novel platform that can be used to treat numerous diseases. These studies reveal that transcription factors can be used to alter gene expression, thereby reprogramming a new cellular phenotype that is eventually maintained by endogenous transcription factors. With this information, we believe it is possible to reprogram the altered phenotype of a diseased cell back to its normal state. Scleroderma in particular, is a non- curable scarring disease with a distinct phenotype that can be defined by its unique gene expression pattern. Here we report the successful induction of a subset of scleroderma-specific genes using predicted and endogenous transcription factors. Microarray data of scleroderma patients was analyzed finding 165 differentially expressed genes. Both DiRE and SynoR were bioinformatic tools employed to determine upstream regulators and downstream gene targets, respectively. Gain of function experiments were carried out as transcription factors were transiently transfected using overexpression vectors in multiple cell types and gene expression was measured via qPCR. 22% of total scleroderma-specific downstream targets were differentially expressed using predicted transcription factors. Additionally, 33% of predicted downstream targets were differentially expressed using endogenously expressed transcription factors. Our data suggest that primary sequence analysis of clusters of transcription factors binding sites in promoters is more predictive than evolutionary and conservation-based approaches alone. Our study represents a novel approach to treating and even curing disease by way of cellular reprogramming

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