KHSRP combines transcriptional and posttranscriptional mechanisms to regulate monocytic differentiation

Abstract

RNA-binding proteins (RBPs) are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes. The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs (Che-RBPs). One of these proteins, KH-type splicing regulatory protein (KHSRP), is a multifunctional RBP that has been implicated in mRNA decay, alternative splicing, and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129. In this study, we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing. KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation. Of note, KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1. Taken together, our analyses revealed the dual DNA- and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.

Multiple roles for AU-rich RNA binding proteins in the development of haematologic malignancies and their resistance to chemotherapy

“…KSRP binds to active promotors in DNA and intronic GU-rich sites in RNA. The activity of this protein contributes to the consistency of transcription and alternative splicing regulation [ 58 ]. In the cytoplasm, KSRP directs transcripts to degradation upon binding to ARE in the 3’UTR [ 73 ].…”

“…Similarly, the activity of KSRP is implicated in cell differentiation. A recent study showed that KSRP protein localized in the nucleus combines regulation of transcription and alternative splicing of targets that play a pivotal role in the coordination of cell differentiation [ 58 ]. The findings demonstrating the role of ARE-binding proteins in the regulation of leukocyte cell fate decisions indicate the significance of the ARE-BP-axis in the early steps of lymphoma development.…”