Divergent Transcription of the Nkx2-5 Locus Generates Two Enhancer RNAs with Opposing Functions
Irene Salamon,
Simone Serio,
Simona Bianco,
Christina Pagiatakis,
Silvia Crasto,
Andrea M. Chiariello,
Mattia Conte,
Paola Cattaneo,
Luca Fiorillo,
Arianna Felicetta,
Elisa di Pasquale,
Paolo Kunderfranco,
Mario Nicodemi,
Roberto Papait,
Gianluigi Condorelli
Affiliations
Irene Salamon
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy
Simone Serio
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (MI), Italy
Simona Bianco
Department of Physics, Federico II University, 80126 Naples, Italy
Christina Pagiatakis
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy
Silvia Crasto
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy; Institute of Genetics and Biomedical Research (Milan Unit), National Research Council of Italy, 20189 Rozzano (MI), Italy
Andrea M. Chiariello
Department of Physics, Federico II University, 80126 Naples, Italy
Mattia Conte
Department of Physics, Federico II University, 80126 Naples, Italy
Paola Cattaneo
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy; Institute of Genetics and Biomedical Research (Milan Unit), National Research Council of Italy, 20189 Rozzano (MI), Italy
Luca Fiorillo
Department of Physics, Federico II University, 80126 Naples, Italy
Arianna Felicetta
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (MI), Italy
Elisa di Pasquale
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy; Institute of Genetics and Biomedical Research (Milan Unit), National Research Council of Italy, 20189 Rozzano (MI), Italy
Paolo Kunderfranco
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy
Mario Nicodemi
Department of Physics, Federico II University, 80126 Naples, Italy; Berlin Institute of Health, Max Delbrück Center, 13125 Berlin, Germany
Roberto Papait
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy; Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy; Corresponding author
Gianluigi Condorelli
Humanitas Clinical and Research Center-IRCCS, 20189 Rozzano (MI), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (MI), Italy; Institute of Genetics and Biomedical Research (Milan Unit), National Research Council of Italy, 20189 Rozzano (MI), Italy; Corresponding author
Summary: Enhancer RNAs (eRNAs) are a subset of long noncoding RNA generated from genomic enhancers: they are thought to act as potent promoters of the expression of nearby genes through interaction with the transcriptional and epigenomic machineries. In the present work, we describe two eRNAs transcribed from the enhancer of Nkx2-5—a gene specifying a master cardiomyogenic lineage transcription factor (TF)—which we call Intergenic Regulatory Element Nkx2-5 Enhancers (IRENEs). The IRENEs are encoded, respectively, on the same strand (SS) and in the divergent direction (div) respect to the nearby gene. Of note, these two eRNAs have opposing roles in the regulation of Nkx2-5: IRENE-SS acts as a canonical promoter of transcription, whereas IRENE-div represses the activity of the enhancer through recruitment of the histone deacetylase sirtuin 1. Thus, we have identified an autoregulatory loop controlling expression of the master cardiac TF NKX2-5, in which one eRNA represses transcription.
