Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors.

Repeat elements can be dysregulated at a genome-wide scale in human diseases. For example, in Ewing sarcoma, hundreds of inert GGAA repeats can be converted into active enhancers when bound by EWS-FLI1. Here we show that fusions between EWS and GGAA-repeat-targeted engineered zinc finger arrays (ZFAs) can function at least as efficiently as EWS-FLI1 for converting hundreds of GGAA repeats into active enhancers in a Ewing sarcoma precursor cell model. Furthermore, a fusion of a KRAB domain to a ZFA can silence GGAA microsatellite enhancers genome wide in Ewing sarcoma cells, thereby reducing expression of EWS-FLI1-activated genes. Remarkably, this KRAB-ZFA fusion showed selective toxicity against Ewing sarcoma cells compared with non-Ewing cancer cells, consistent with its Ewing sarcoma-specific impact on the transcriptome. These findings demonstrate the value of ZFAs for functional annotation of repeats and illustrate how aberrant microsatellite activities might be regulated for potential therapeutic applications

Analogy-based domain analysis approach to software reuse

Domain analysis is an expansion of conventional requirements analysis. Domain analysis can support effective software reuse. However, domain analysis is time consuming and is limited to a particular application area. Analogical approaches to software reuse, on the other hand, often occur across domains. Analogical problem solving is a process of transferring knowledge from a well-understood base domain to a new target problem area. Analogy can facilitate software reuse for poorly understood problems or new application areas. Analogy shares similar concepts with reuse and some analogy theories have been applied to software reuse. However, current research on software analogy often overlooks the importance of analysis for the base domain and does not consider some critical aspects of analogy concepts. Reuse must be based on high quality artifacts, especially reuse across domains. This paper presents an approach to integrate domain analysis and analogy methods. In our view, domain analysis and software analogy have complementary roles. Domain analysis is regarded as a process to identify and supply necessary information for analogical transfer. Software analogy can provide the analyst with similar problems and solutions to reuse previous domain analysis knowledge or artifacts for a new domain. This paper presents case studies to demonstrate the increase of efficiency in applying the approach. Evaluation of the approach from various perspectives is also reported