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Genome-wide RNA structure changes during human neurogenesis modulate gene regulatory networks

ABSTRACT: RNAs structures play central roles in various cellular processes, and can be remodeled upon binding to cellular factors such as RNA binding proteins (RBP). However, how widespread this remodeling is and whether structural changes can serve as additional regulatory steps for other regulators remains under-explored. Here, we assayed RNA structural dynamics, gene expression, translation and decay during different stages of human neuronal differentiation to understand the impact of RNA structures in stem cell regulation. RBP binding resulted in wide-spread RNA structure changes during early neuronal differentiation. Structure changes act as a common mechanism for RBPs to modulate the binding of additional RBPs and miRNAs to coordinate gene expression temporally. In particular, we showed that PUM2 binding on LIN28A resulted in RNA structure changes that enabled miR-30 binding, leading to downregulation of LIN28A. Compensatory mutagenesis experiments that lock specific structural states confirmed the importance of PUM2-induced structure changes in miR-30 regulation. This systematic study broadens our understanding of RNA structural dynamics during human neuronal differentiation and illustrates the wide-spread and complex role of RBPs in regulating RNA structures for gene regulation during human development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236224 | GEO | 2023/07/01

REPOSITORIES: GEO

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Genome-wide structure changes during neuronal differentiation drive gene regulatory networks

Project description:RNAs structures play central roles in various cellular processes, and can be remodeled upon binding to cellular factors such as RNA binding proteins (RBP). However, how widespread this remodeling is and whether structural changes can serve as additional regulatory steps for other regulators remains under-explored. Here, we assayed RNA structural dynamics, gene expression, translation and decay during different stages of human neuronal differentiation to understand the impact of RNA structures in stem cell regulation. RBP binding resulted in wide-spread RNA structure changes during early neuronal differentiation. Structure changes act as a common mechanism for RBPs to modulate the binding of additional RBPs and miRNAs to coordinate gene expression temporally. In particular, we showed that PUM2 binding on LIN28A resulted in RNA structure changes that enabled miR-30 binding, leading to downregulation of LIN28A. Compensatory mutagenesis experiments that lock specific structural states confirmed the importance of PUM2-induced structure changes in miR-30 regulation. This systematic study broadens our understanding of RNA structural dynamics during human neuronal differentiation and illustrates the wide-spread and complex role of RBPs in regulating RNA structures for gene regulation during human development.

2020-08-23 | GSE156671 | GEO

Global analysis of the RNA-protein interaction and RNA secondary structure landscapes of the Arabidopsis nucleus

Project description:Post-transcriptional regulation in eukaryotes requires cis- and trans-acting features and factors including RNA secondary structure, and RNA-binding proteins (RBPs). However, a comprehensive view of the structural and RBP interaction landscape of RNAs in the nucleus has yet to be compiled for any organism. Here, we use our ribonuclease-mediated structure and RBP binding site mapping approach on Arabidopsis seedling nuclei in vivo to globally profile these features within the nuclear compartment. We reveal opposing patterns of secondary structure and RBP binding levels throughout native messenger RNAs that demarcate alternative splicing and polyadenylation. We also uncover a collection of protein bound sequence motifs, and identify their structural contexts, co-occurrences in transcripts encoding functionally related proteins, and interactions with putative RBPs. Finally, we identify a nuclear role for the chloroplast RBP, CP29A. In total, we provide the first simultaneous view of the RNA secondary structure and RBP interaction landscapes in a eukaryotic nucleus. Protein interaction profile sequencing (PIP-seq) in Arabidopsis seedling nuclei. These are crosslinked with formaldehyde and treated with two RNases (ssRNase and dsRNase) with two replicates

2014-12-16 | E-GEOD-58974 | biostudies-arrayexpress

Global signatures of protein binding on structural RNAs in Saccharomyces cerevisiae

Project description:Protein binding is essential to the transport, decay and regulation of almost all RNA molecules. However, the structural preference of protein binding on RNAs and their cellelar functions and dynamics upon changing environmental condictions are poorly understood. Here, we integrated various high-throughput data and introduced a computational framework to describe the global interactions between RNA binding proteins (RBPs) and structured RNAs in yeast at single-nucleotide resolution. We found that on average, in terms of percent total lengths, ~15% of mRNA untranslated regions (UTRs), ~37% of canonical ncRNAs and ~11% of long ncRNA (lncRNAs) are bound by proteins. The RBP binding sites, in general, tend to occur at single-stranded loops, with evolutionarily conserved signatures, and often facilitate a specific RNA structure conformation in vivo. We found that four nucleotide modifications of tRNA are significantly associated with RBP binding. We also identified various structural motifs bound by RBPs in the UTRs of mRNAs, associated with localization, degradation and stress responces. Moreover, we identified >200 novel lncRNAs bound by RBPs, and about half of them contain conserved secondary structures. We present the first ensemble pattern of RBP binding sites in the structured noncoding regions of a eukaryotic genome, emphasizing their structural context and cellular functions. Duplicate gPAR-CLIP libraries were sequenced from yeast strains for each of three conditions: log-phase growth, growth after 2 hour glucose starvation, and growth after 2 hour nitrogen starvation. polyA RNAs were isolated for all conditions. Total RNA were isolated from log phase growth conditions. Sucrose gradient fractionation was performed: some RNAs were isolated from the "light" fraction (lighter than 40S ribosome) and some from the "heavy" fraction. gPAR-CLIP libraries were used to determine regions of RNA bound by proteins.

2013-07-15 | E-GEOD-48888 | biostudies-arrayexpress

Global analysis of the RNA-protein interaction and RNA secondary structure landscapes of the Arabidopsis nucleus

2014-12-16 | GSE58974 | GEO

Embryonic lumenogenesis is controlled by selective mRNA decay triggered by LIN28A relocation [RNA-Seq]

Project description:The naïve pluripotent epiblast cells become polarized into a rosette-like structure, followed by irreversible transition into primed pluripotency during one of the fastest morphological switches termed lumenogenesis. This requires rapid decay of pluripotency-associated mRNAs, but the underlying mechanism remains unknown. Guided by machine learning and metabolic RNA sequencing, we identified RNA binding proteins (RBPs), especially LIN28A, as primary mRNA decay factors. To understand if RBP dynamics steer embryogenesis, we used mRNA-RBP interactome capture during naïve-rosette-epiblast-gastrulation progression. We identified a dramatic increase in LIN28A mRNA binding, driven by its nucleolus-to-cytoplasm translocation during the naïve-primed pluripotency transition. Cytoplasmic LIN28A binds to 3’UTRs of pluripotency-associated mRNAs to directly stimulate their decay, and thereby progression to lumenogenesis. Accordingly, forced nuclear retention of LIN28A impeded lumenogenesis, causing an unforeseen embryonic multiplication and impaired gastrulation. This reveals selective mRNA decay, driven by nucleo-cytoplasmic RBP translocation, as an intrinsic mechanism for cell identity switch that controls embryonic timing of lumenogenesis.

2024-03-01 | GSE169553 | GEO

Embryonic lumenogenesis is controlled by selective mRNA decay triggered by LIN28A relocation [Quant-Seq]

2024-03-01 | GSE169552 | GEO

Embryonic lumenogenesis is controlled by selective mRNA decay triggered by LIN28A relocation [miCLIP]

2024-03-01 | GSE169549 | GEO

Embryonic lumenogenesis is controlled by selective mRNA decay triggered by LIN28A relocation [iCLIP]

2024-03-01 | GSE169547 | GEO

Embryonic lumenogenesis is controlled by selective mRNA decay triggered by LIN28A relocation [Slam-Seq]

2024-03-01 | GSE169554 | GEO

PIE-Seq: Identifying RNA-binding Protein Targets by Dual RNA-deaminase Editing and Sequencing

Project description:RNA-binding proteins (RBPs) are essential for posttranscriptional gene regulation, but it remains a challenge to identify RNA targets of RBPs from specific cell types. Here we present PIE-Seq to investigate Protein-RNA Interaction with dual-deaminase Editing and Sequencing by conjugating C-to-U and A-to-I RNA deaminases to RBPs. We benchmark the method and demonstrate its sensitivity in single cells, its application in the developing brain, and its scalability with 25 human RBPs involved in diverse biological functions. Bulk PIE-Seq reveals canonical binding features and target genes for RBPs such as PUM2 and NOVA1, and nominates new target genes for most tested RBPs such as SRSF1 and TDP-43/TARDBP. Integrative analyses show that homologous RBPs frequently bind to comparable sequences and target gene sets while different RBP families bind to distinct targets, indicating that PIE-Seq is robust to uncovering RBP targets. Single-cell PIE-PUM2 uncovers comparable targets to bulk samples and applying PIE-PUM2 to the developing mouse neocortex identifies neural-progenitor- and neuron-specific target genes. In summary, the dual-deaminase PIE-Seq joins the editable nucleotide space for single editors and provides an orthogonal approach and resource to uncover RBP targets in mice and human cells.

2023-05-17 | GSE155844 | GEO

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