simplifyEnrichment:A Bioconductor Package for Clustering and Visualizing Functional Enrichment Results

Functional enrichment analysis or gene set enrichment analysis is a basic bioinformatics method that evaluates the biological importance of a list of genes of interest.However,it may produce a long list of significant terms with highly redundant information that is difficult to summarize.Current tools to simplify enrichment results by clustering them into groups either still produce redundancy between clusters or do not retain consistent term similarities within clusters.We propose a new method named binary cut for clustering similarity matrices of functional terms.Through comprehensive benchmarks on both simulated and real-world datasets,we demonstrated that binary cut could efficiently cluster functional terms into groups where terms showed consistent similarities within groups and were mutually exclusive between groups.We compared binary cut clustering on the similarity matrices obtained from different similarity measures and found that semantic similarity worked well with binary cut,while similarity matrices based on gene overlap showed less consistent patterns.We implemented the binary cut algorithm in the R package simplifyEnrichment,which additionally provides functionalities for visualizing,summarizing,and comparing the clustering.The simplifyEnrichment package and the documentation are available at https://bioconductor.org/packages/simplifyEnrichment/.

Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity

Histone deacetylase 6 （HDAC6）, a predominantly cyto- plasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 can- not be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 （MYH9）, heat shock cognate pro- tein 70 （HscT0）, and dnaJ homolog subfamily A member 1 （DNAJA1）, were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6- mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of proteinacetylation with the capability of coordinating various cellular functions.

Repurposing an old anti-fungal drug as a Hedgehog inhibitor

It requires approximately 800 million dollars(US)and 10 years to successfully bring a drug from the laboratory bench into the clinic(DiMasi et al.,2003).Thus,the breakthrough discovery of today will not be available in the clinic for many years,and many dollars,after this initial discovery.One potential way to speed up this drug developmental cycle is by repurposing drugs that have been previously approved for an alternate clinical indication.With this goal in mind,Beachy and colleagues set out to identify a drug with efficacy against tumors that were dependant on the Hedgehog(HH)signaling pathway.They reported in the April issue of a leading cancer research journal that Itraconazole,a commonly used antifungal drug,can be turned against HH’s signaling function(Kim et al.,2010).It has been estimated that 25%of all human tumors may be HH dependent(Teglund et al,2010).