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Cohesin complexes have been extensively studied for their roles in sister chromatid cohesion during cell division, and in addition, regulate transcription throughmultiple mechanisms. Together with Nipped-B, a cohesin-loading factor that facilitates enhancer-promoter interactions, cohesins bind many activated enhancers but seem to preferentially associate with a subset of active genes linked to growth control and development [1]. This is consistent with findings that mutations in Nipped-B lead to Cornelia de Lange syndrome (CdLS), a genetic condition accompanied by developmental abnormalities and intellectual delay. The mechanism by which cohesin and Nipped B “choose” their gene targets from all the active genes has been elusive. A recent study by Swain et al. [2] provides important insights into this selection process. Using chromatin immunoprecipitations, followed by deep sequencing (ChIP-seq), bioinformatics, and binding studies, Swain et al. [2] identify two RNA-binding proteins, TBPH and Lark, that help guide the selection of genes bound by cohesin and Nipped-B. This is achieved by binding to nascent RNA transcripts and subsequent stabilization of cohesin and Nipped-B complexes on DNA (Fig 1). TBPH is theDrosophila homolog of TAR DNA-binding protein (TARDP, or TDP-43), which harbors nuclear localization and export signals (NLS, NES), two RNA recognitionmotifs (RRMs), and a C terminus low complexity, prion-like domain [3]. It has been implicated in multiple aspects of gene expression, including transcription, splicing, mRNA transport, association with RNA stress granules (SGs), and translation [4]. Similar to TBPH, Lark, also known as RBM4, is an RNA-binding protein involved in splicing and translation regulation, comprising two RRM domains and a low complexity C terminus domain that are separated by a C2HC Zn finger-bindingmotif [5]. Multiple lines of evidence led the authors to hypothesize that RNA-binding proteins may help define the repertoire of genes bound by cohesin and Nipped-B complexes. First, TBPH/ TDP-43 has been shown to bind UG repeats within its RNA targets [6–8], while Nipped-B associates preferentially with genes containing TG repeats downstream of transcription start sites [9]. Second, TDP-43 was found to regulate the transcription of the testis-specificmouse acrv1 gene by binding to TGTGTG sequences within its promoter. Deletion of RRM1 or disabling RNA binding compromise TDP-43’s repressor function, suggesting that an RNA intermediate may be involved in its role as a transcriptional repressor [10]. Third, RNA immunoprecipitation experiments identified several transcripts produced by Nipped-B-bound genes as Lark targets [11]. Lark was also found to associate with transcripts of cohesin-bound genes by RNA affinity chromatography and mass spectrometry approaches [2]. To test this intriguing hypothesis, Swain et al. [2] used a ChIP-seq approach and found that cohesin, Nipped B, TBPH, and Lark bind genes and regulatory sequences such as enhancers

A Helping Hand: RNA-Binding Proteins Guide Gene-Binding Choices by Cohesin Complexes