DNA- and RNA-Binding Proteins Linked Transcriptional Control and Alternative Splicing Together in a Two-Layer Regulatory Network System of Chronic Myeloid Leukemia

Abstract

DNA- and RNA-binding proteins (DRBPs) typically possess multiple functions to bind both DNA and RNA and regulate gene expression from more than one level. They are controllers for post-transcriptional processes, such as splicing, polyadenylation, transportation, translation, and degradation of RNA transcripts in eukaryotic organisms, as well as regulators on the transcriptional level. Although DRBPs are reported to play critical roles in various developmental processes and diseases, it is still unclear how they work with DNAs and RNAs simultaneously and regulate genes at the transcriptional and post-transcriptional levels. To investigate the functional mechanism of DRBPs, we collected data from a variety of databases and literature and identified 118 DRBPs, which function as both transcription factors (TFs) and splicing factors (SFs), thus called DRBP-SF. Extensive investigations were conducted on four DRBP-SFs that were highly expressed in chronic myeloid leukemia (CML), heterogeneous nuclear ribonucleoprotein K (HNRNPK), heterogeneous nuclear ribonucleoprotein L (HNRNPL), non-POU domain–containing octamer–binding protein (NONO), and TAR DNA-binding protein 43 (TARDBP). By integrating and analyzing ChIP-seq, CLIP-seq, RNA-seq, and shRNA-seq data in K562 using binding and expression target analysis and Statistical Utility for RBP Functions, we discovered a two-layer regulatory network system centered on these four DRBP-SFs and proposed three possible regulatory models where DRBP-SFs can connect transcriptional and alternative splicing regulatory networks cooperatively in CML. The exploration of the identified DRBP-SFs provides new ideas for studying DRBP and regulatory networks, holding promise for further mechanistic discoveries of the two-layer gene regulatory system that may play critical roles in the occurrence and development of CML.

Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation

“…A recent study suggests more than 100 TFs are actively involved in splicing through their DRBP function 66 . The ability to interact with both DNA and RNA is either conferred by a combination of specialized domains, e.g.…”

“…DNA- and RNA-binding is a strong indicator for sub-compartmental clustering of transcriptional processes, e.g. for co-transcriptional splicing 66 or miRNA processing. The latter was suggested for SAFB2 81,82 as a bona fide example of a DRBP 67 .…”

Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation

“…A recent study suggests more than 100 TFs are actively involved in splicing through their DRBP function ( 43 ). The ability to interact with both DNA and RNA is either conferred by a combination of specialized domains, for example, in Sox2 ( 10 ) or SAFB2 ( 44 ) or by the dual exploitation of one domain ( 12 , 45 ).…”

“…Similar to the emerging role of circRNAs for RBPs ( 56 ), RNAs may also act as sponges for excessive DBPs ( 57 ) via IDR interactions. DNA- and RNA-binding is a strong indicator for subcompartmental clustering of transcriptional processes, for example, for co-transcriptional splicing ( 43 ) or miRNA processing. The latter was suggested for SAFB2 ( 58 , 59 ) as a bona fide example of a DRBP ( 44 ).…”

BindCompare: A Novel Integrated protein-nucleic Acid Binding Analysis Platform

“…Transcription factors (TFs) regulate RNA transcription from DNA, and RNAbinding proteins (RBPs) form the bulk of nucleic acid-binding proteins that control splicing and nuclear export. Multiple nucleic acid binding proteins function together to co-regulate specific sets of target genes, which are often called gene regulatory networks (GRNs) (Oksuz et al 2023;Wang et al 2022). High-throughput genomic technologies have generated hundreds of data sets that provide information regarding DNA and RNA targets of individual nucleic acid binding proteins, helping decipher the combinatorial function of TFs and RBPs in regulating specific GRNs (Salma et al 2023;Martin et al 2023;König et al 2012).…”