The role of DOCK10 in the regulation of the transcriptome and aging

DOCK10, a guanine-nucleotide exchange factor (GEF) for Rac1 and Cdc42 Rho GTPases whose expression is induced by interleukin-4 (IL-4) in B cells, is involved in B cell development and function according to recent studies performed in Dock10-knockout (KO) mice. To investigate whether DOCK10 is involved in regulation of the transcriptome, changes in the gene expression profiles (GEPs) were studied by microarray in three cellular models: DOCK10 expression induced by doxycycline (dox) withdrawal in a stable inducible HeLa clone, DOCK10 expression induced by transient transfection of 293T cells, and wild type (WT) versus KO mouse spleen B cells (SBC). In all three systems, DOCK10 expression determined moderate differences in the GEPs, which were functionally interpreted by gene set enrichment analysis (GSEA). Common signatures significantly associated to expression of DOCK10 were found in all three systems, including the upregulated targets of HOXA5 and the SWI/SNF complex, and EGF signaling. In SBC, Dock10 expression was associated to enrichment of gene sets of Cmyb, integrin, IL-4, Wnt, Rac1, and Cdc42 pathways, and of cellular components such as the immunological synapse and the cell leading edge. Transcription of genes involved in these pathways likely acts as a feedforward mechanism downstream of activation of Rac1 and Cdc42 mediated by DOCK10. Interestingly, a senescence gene set was found significantly associated to WT SBC. To test whether DOCK10 is related to aging, we set out to analyse the survival of the mouse colony, which led to the finding that Dock10-KO mice lived longer than WT mice. Moreover, Dock10-KO mice showed slower loss of their coat during aging. These results indicate a role for Dock10 in senescence. These novel roles of DOCK10 in the regulation of the transcriptome and aging deserve further exploration.