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Background  Recently, it has become clear that some promoters function as long-range regulators of gene expression. However, direct and quantitative assessment of enhancer activity at long intergenic noncoding RNA (lincRNA) or mRNA gene bodies has not been performed. To unbiasedly assess the enhancer capacity across lincRNA and mRNA loci, we performed a massively parallel reporter assay (MPRA) on six lincRNA loci and their closest protein-coding neighbors.    Results  For both gene classes, we find significantly more MPRA activity in promoter regions than in gene bodies. However, three lincRNA loci,  Lincp21 ,  LincEnc1 , and  Peril , and one mRNA locus,  Morc2a , display significant enhancer activity within their gene bodies. We hypothesize that such peaks may mark long-range enhancers, and test this in vivo using RNA sequencing from a knockout mouse model and high-throughput chromosome conformation capture (Hi-C). We find that ablation of a high-activity MPRA peak in the  Peril  gene body leads to consistent dysregulation of  Mccc1  and  Exosc9  in the neighboring topologically associated domain (TAD). This occurs irrespective of  Peril  lincRNA expression, demonstrating this regulation is DNA-dependent. Hi-C confirms long-range contacts with the neighboring TAD, and these interactions are altered upon  Peril  knockout. Surprisingly, we do not observe consistent regulation of genes within the local TAD. Together, these data suggest a long-range enhancer-like function for the  Peril  gene body.    Conclusions  A multi-faceted approach combining high-throughput enhancer discovery with genetic models can connect enhancers to their gene targets and provides evidence of inter-TAD gene regulation.    Electronic supplementary material  The online version of this article (10.1186/s13059-018-1589-8) contains supplementary material, which is available to authorized users.

Enhancers in the Peril lincRNA locus regulate distant but not local genes