Computational analysis of crosstalk between transcriptional regulators and RNA-binding proteins suggests mutual regulation of polycomb proteins and SRSF1 influencing adult hippocampal neurogenesis

Abstract

Background: Adult hippocampal neurogenesis (AHN) is a clinically significant neural phenomenon. Understanding its molecular regulation would be important. In this regard, most studies have focused on transcriptional regulators (TRs), epigenetic modifiers, or non-coding RNAs. RNA-binding proteins (RBPs) have emerged as dominant molecular regulators. It would be significant to understand the potential cross-talk between RBPs and TRs, which could influence AHN.

Methods: The present study employed computational analyses to identify RBPs and TRs regulating AHN, followed by the analysis of their interaction networks and detection of hub proteins. Next, the potential mutual regulation of hub TRs and RBPs was analyzed. Additionally, hippocampal genes differentially expressed upon exercise were analyzed for potential regulation by the identified TRs and RBPs.

Results: 105 TRs and 26 RBPs were found to influence AHN, which could also form interactive networks. Polycomb complex proteins were among the TR network hubs, while HNRNP and SRSF family members were among the hub RBPs. Further, the polycomb complex proteins and SRSF1 could have a mutual regulatory relationship, suggesting a cross-talk between epigenetic/transcriptional and post-transcriptional regulatory pathways. A number of exercise-induced hippocampal genes were also found to be potential targets of the identified TRs and RBPs.

Conclusion: SRSF1 may influence post-transcriptional stability, localization, and alternative splicing patterns of polycomb complex transcripts, and the polycomb proteins may in turn epigenetically influence the SRSF1. Further experimental validation of these regulatory loops/networks could provide novel insights into the molecular regulation of AHN, and unravel new targets for disease-treatment.

Keywords: Adult hippocampal neurogenesis (AHN); Physical exercise; Polycomb complex; Post-transcriptional regulation; RNA-binding proteins (RBPs); SRSF.

Fig. 1

Work-flow of the present study. AHN-related genes were retrieved from Mammalian Adult Neurogenesis Gene Ontology (MANGO) database, followed by identification of transcriptional regulators and RNA-binding proteins influencing these genes. Subsequently, inter-molecular interactions of these proteins were analyzed and the hub-proteins were identified. Further, potential mutual-regulation of the hub proteins was studied, which showed the interaction between transcriptional and post-transcriptional regulators influencing AHN

Fig. 2

Number of transcriptional regulators (TRs) and RNA-binding proteins (RBPs) associated with adult hippocampal neurogenesis (AHN). Genes associated with AHN (obtained from MANGO database) were compared with known TRs and RBPs retrieved from respective databases

Fig. 3

Hub proteins of transcriptional regulator (TRs) and RNA-binding protein (RBPs) networks. The top ten hub proteins of the TR (a) and RBP (b) networks having extensive interconnections are shown

Fig. 4

A model of mutual-regulation of SRSF1 and polycomb gene transcripts influencing AHN. SRSF1 could be involved in post-transcriptional regulation of polycomb gene transcripts, and the polycomb complex could in turn regulate the transcription of SRSF1. These proteins could also influence multiple aspects of AHN. Further, SRSF1 and polycomb complex proteins could influence exercise-induced AHN by altering their target gene expression patterns. Hence, potential cross-talk between transcriptional and post-transcriptional regulators may influence AHN