IntroductionFat-tail in sheep is considered as an important energy reservoir to provide energy as a survival buffer during harsh challenges. However, fat-tail is losing its importance in modern sheep industry systems and thin-tailed breeds are more desirable. Using comparative transcriptome analysis to compare fat-tail tissue between fat- and thin-tailed sheep breeds provides a valuable approach to study the complex genetic factors associated with fat-tail development. However, transcriptomic studies often suffer from issues with reproducibility, which can be improved by integrating multiple studies based on a meta-analysis.MethodsHence, for the first time, an RNA-Seq meta-analysis on sheep fat-tail transcriptomes was performed using six publicly available datasets.Results and discussionA total of 500 genes (221 up-regulated, 279 down-regulated) were identified as differentially expressed genes (DEGs). A jackknife sensitivity analysis confirmed the robustness of the DEGs. Moreover, QTL and functional enrichment analysis reinforced the importance of the DEGs in the underlying molecular mechanisms of fat deposition. Protein-protein interactions (PPIs) network analysis revealed the functional interactions among the DEGs and the subsequent sub-network analysis led to identify six functional sub-networks. According to the results of the network analysis, down-regulated DEGs in green and pink sub-networks (like collagen subunits IV, V, and VI, integrins 1 and 2,SCD, SCD5, ELOVL6, ACLY, SLC27A2, andLPIN1) may impair lipolysis or fatty acid oxidation and cause fat accumulation in tail. On the other hand, up-regulated DEGs, especially those are presented in green and pink sub-networks (likeIL6, RBP4, LEPR, PAI-1, EPHX1, HSD11B1, andFMO2), might contribute to a network controlling fat accumulation in the tail of sheep breed through mediating adipogenesis and fatty acid biosynthesis. Our results highlighted a set of known and novel genes/pathways associated with fat-tail development, which could improve the understanding of molecular mechanisms behind fat deposition in sheep fat-tail.