Dual DNA/RNA-binding factor regulates dynamics of hnRNP splicing condensates

Abstract

Despite decades of research, mechanisms by which co-transcriptional alternative splicing events are targeted to the correct genomic locations to drive cell fate decisions remain unknown. By combining structural and molecular approaches, we define a new mechanism by which an essential transcription factor (TF) targets co-transcriptional splicing through physical and functional interaction with RNA and RNA binding proteins (RBPs). We show that an essential TF co-transcriptionally regulates sex-specific alternative splicing by directly interacting with a subset of target RNAs on chromatin and modulating the dynamics of hnRNPA2 homolog nuclear splicing condensates.

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

“…Arid5a perfectly colocalizes with some of the bright heterochromatin dots, indicating a close proximity to silenced chromatin. Together with our iCLIP2 data, this suggests that Arid5a might use its dual nucleic acid–binding capability to interact with DNA and pre-mRNA simultaneously, for example, to detect transcribed loci and then modulate transcriptional repression as it was described earlier ( 17 , 18 ) and very recently for TF with an RBP activity ( 42 ).

Figure 8 Subcellular localization and RNA - binding of Arid5a.

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BindCompare: A Novel Integrated Protein-Nucleic Acid Binding Analysis Platform

“…One can also do individual chromosome-wide binding analysis with BindCompare. We compared the binding of the male X-chromosome enriched Drosophila transcription factor CLAMP at genomic locations on DNA (# GSE220053) with its RNA targets (# GSE205987) in male cells (Ilik et al 2013; Soruco et al 2013; Ray et al 2024). Using BindCompare for individual chromosome-wise overlap profiles, we show that CLAMP-DNA peaks overlapping with RNA peaks are more frequently distributed on X-chromosomes than autosomes ( Supp.…”