Gene expression in mammalian cells is known to subject regulation at both the transcriptional and post-transcription levels.Studies on transcriptional control have been traditionally focused on promoters and enhances as well as short and long-distance communication between various regulatory elements.Interestingly, recent studies have implicated regulatory RNA in transcriptional control, including eRNA in mediating promoter-enhancer interactions and long non-coding RNA (IncRNA) that serve as a scaffold for the recruitment and nucleation of regulatory transcription complexes.The involvement of RNA in regulated gene expression must enlist some specific RNA binding proteins to bridge molecular assemblies at various genomic locations.Increasing evidence suggests that many RNA binding proteins and ribonucleoprotein particles (RNPs) are multi-tasking beyond their traditional roles in RNA processing in mammalian cells.RBFox2 is a RNA binding protein with tissue-restricted expression in the brain and heart.By conditional knockout in mouse cardiaomyocytes, we demonstrate that RBFox2 is essential for heart function, and as expected from its established role in regulated splicing, RBFox2 elicits its position-dependent effects on alternative splicing of genes critical for maintaining the structure of the contractile apparatus and excitation-contraction coupling in the heart.Using a battery of functional genomics approaches, we further uncover additional regulatory roles of RBFox2 in RNA metabolism, including its prevalent binding to the 3UTR to modulate microRNA function.Strikingly, our global analysis also reveals a wide involvement of RBFox2 in transcriptional repression, which is mediated by its interaction with chromatin associated nascent RNA and the recruited general transcription co-repressor NcoR.Thus, besides promoters and enhancers, the composition of gene body sequences can also provide critical signals for transcriptional control via specific RNA binding proteins.