Enhancers with tissue-specific activity are enriched in intronic regions

Tissue function and homeostasis reflect the gene expression signature by which the combination of ubiquitous and tissue-specific genes contribute to the tissue maintenance and stimuli-responsive function. Enhancers are central to control this tissue-specific gene expression pattern. Here, we explore the correlation between the genomic location of enhancers and their role in tissue-specific gene expression. We find that enhancers showing tissue-specific activity are highly enriched in intronic regions and regulate the expression of genes involved in tissue-specific functions, whereas housekeeping genes are more often controlled by intergenic enhancers, common to many tissues. Notably, an intergenic-to-intronic active enhancers continuum is observed in the transition from developmental to adult stages: the most differentiated tissues present higher rates of intronic enhancers, whereas the lowest rates are observed in embryonic stem cells. Altogether, our results suggest that the genomic location of active enhancers is key for the tissue-specific control of gene expression.
S.A. is a Serra-Hunter Fellow since 2021. S.A. is supported by a fellowship from the Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement (Generalitat de Catalunya) (BP-2017-00176). B.B. is supported by the fellowship 2017FI_B00722 from the Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement (Generalitat de Catalunya) and the European Social Fund (ESF). P.V-M. is supported by an FPI PhD fellowship (FPI-BES-2016-077706) part of the “Unidad de Excelencia María de Maeztu” funded by the Ministerio de Economía, Industria y Competitividad, Gobierno de España (MINECO) (ref: MDM-2014-0370). J.B. is funded by PID2019-110933GB-I00/AEI/10.13039/501100011033 awarded by the Agencia Estatal de Investigación (AEI) and with the support of Secretaria d'Universitats i Recerca de la Generalitat de Catalunya (GRC 2017 SGR 702). The DCEXS at UPF is part of the “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX2018-000792-M).