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Abstract Hoxa5plays numerous roles in development, but its downstream molecular effects are mostly unknown. We applied bulk RNA-seq assays to characterize the transcriptional impact of the loss ofHoxa5gene function in seven different biological contexts, including developing respiratory and musculoskeletal tissues that present phenotypes inHoxa5mouse mutants. This global analysis revealed few common transcriptional changes, suggesting that HOXA5 acts mainly via the regulation of context-specific effectors. However,Hoxgenes themselves appeared as potentially conserved targets of HOXA5 across tissues. Notably, a trend toward reduced expression ofHoxAgenes was observed inHoxa5null mutants in several tissue contexts. Comparative analysis of epigenetic marks along theHoxAcluster in lung tissue from two differentHoxa5mutant mouse lines revealed limited effect of either mutation indicating thatHoxa5gene targeting did not significantly perturb the chromatin landscape of the surroundingHoxAcluster. Combined with the shared impact of the twoHoxa5mutant alleles on phenotype andHoxexpression, these data argue against the contribution of localciseffects toHoxa5mutant phenotypes and support the notion that the HOXA5 protein acts intransin the control ofHoxgene expression.