SUMMARY Increasing evidence suggests that transcriptional control and chromatin activities at large involve regulatory RNAs, which likely enlist specific RNA-binding proteins (RBPs). Although multiple RBPs have been implicated in transcription control, it has remained unclear how extensively RBPs directly act on chromatin. We embarked on a large-scale RBP ChIP-seq analysis, revealing widespread RBP presence in active chromatin regions in the human genome. Like transcription factors (TFs), RBPs also show strong preference for hotspots in the genome, particularly gene promoters, where their association is frequently linked to transcriptional output. Unsupervised clustering reveals extensive co-association between TFs and RBPs, as exemplified by YY1, a known RNA-dependent TF, and RBM25, an RBP involved in splicing regulation. Remarkably, RBM25 depletion attenuates all YY1-dependent activities, including chromatin binding, DNA looping, and transcription. We propose that various RBPs may enhance network interaction through harnessing regulatory RNAs to control transcription.
The exosome functions in the degradation of diverse RNA species, yet how it is negatively regulated remains largely unknown. Here, we show that NRDE2 forms a 1:1 complex with MTR4, a nuclear exosome cofactor critical for exosome recruitment, via a conserved MTR4-interacting domain (MID). Unexpectedly, NRDE2 mainly localizes in nuclear speckles, where it inhibits MTR4 recruitment and RNA degradation, and thereby ensures efficient mRNA nuclear export. Structural and biochemical data revealed that NRDE2 interacts with MTR4's key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome as well as proteins important for MTR4 recruitment, such as the cap-binding complex (CBC) and ZFC3H1. Functionally, MID deletion results in the loss of self-renewal of mouse embryonic stem cells. Together, our data pinpoint NRDE2 as a nuclear exosome negative regulator that ensures mRNA stability and nuclear export.
Early embryogenesis relies on maternally inherited mRNAs. Although the mechanism of maternal mRNA degradation during maternal-to-zygotic transition (MZT) has been extensively studied in vertebrates, how the embryos maintain maternal mRNA stability remains unclear. Here, we identify Igf2bp3 as an important regulator of maternal mRNA stability in zebrafish. Depletion of maternal igf2bp3 destabilizes maternal mRNAs prior to MZT and leads to severe developmental defects, including abnormal cytoskeleton organization and cell division. However, the process of oogenesis and the expression levels of maternal mRNAs in unfertilized eggs are normal in maternal igf2bp3 mutants. Gene ontology analysis revealed that these functions are largely mediated by Igf2bp3-bound mRNAs. Indeed, Igf2bp3 depletion destabilizes while its overexpression enhances its targeting maternal mRNAs. Interestingly, igf2bp3 overexpression in wild-type embryos also causes a developmental delay. Altogether, these findings highlight an important function of Igf2bp3 in controlling early zebrafish embryogenesis by binding and regulating the stability of maternal mRNAs.
The RNA‐binding protein ALYREF plays key roles in nuclear export and also 3′‐end processing of polyadenylated mRNAs, but whether such regulation also extends to non‐polyadenylated RNAs is unknown. Replication‐dependent (RD)‐histone mRNAs are not polyadenylated, but instead end in a stem‐loop (SL) structure. Here, we demonstrate that ALYREF prevalently binds a region next to the SL on RD‐histone mRNAs. SL‐binding protein (SLBP) directly interacts with ALYREF and promotes its recruitment. ALYREF promotes histone pre‐mRNA 3′‐end processing by facilitating U7‐snRNP recruitment through physical interaction with the U7‐snRNP‐specific component Lsm11. Furthermore, ALYREF, together with other components of the TREX complex, enhances histone mRNA export. Moreover, we show that 3′‐end processing promotes ALYREF recruitment and histone mRNA export. Together, our results point to an important role of ALYREF in coordinating 3′‐end processing and nuclear export of non‐polyadenylated mRNAs.
To ensure efficient and accurate gene expression, pre-mRNA processing and mRNA export need to be balanced. However, how this balance is ensured remains largely unclear. Here, we found that SF3b, a component of U2 snRNP that participates in splicing and 3′ processing of pre-mRNAs, interacts with the key mRNA export adaptor THO in vivo and in vitro. Depletion of SF3b reduces THO binding with the mRNA and causes nuclear mRNA retention. Consistently, introducing SF3b binding sites into the mRNA enhances THO recruitment and nuclear export in a dose-dependent manner. These data demonstrate a role of SF3b in promoting mRNA export. In support of this role, SF3b binds with mature mRNAs in the cells. Intriguingly, disruption of U2 snRNP by using a U2 antisense morpholino oligonucleotide does not inhibit, but promotes, the role of SF3b in mRNA export as a result of enhanced SF3b-THO interaction and THO recruitment to the mRNA. Together, our study uncovers a U2-snRNPindependent role of SF3b in mRNA export and suggests that SF3b contributes to balancing pre-mRNA processing and mRNA export.SF3b | THO | mRNA export | pre-mRNA processing | U2 snRNP I n eukaryotes, the nascent pre-mRNA transcripts undergo multiple processing steps in the nucleus before mRNAs are exported to the cytoplasm for translation. Accumulating evidence suggests that pre-mRNA processing and mRNA export need to be balanced to ensure efficient and accurate gene expression (1-7). When splicing factors are limited or when mRNA export factors are present in excess, even unspliced pre-mRNAs are leaked to the cytoplasm (1-3). On the contrary, down-regulation of nuclear export factors results in nuclear retention of fully processed mRNAs that are ultimately subject to degradation (4-7). Thus, maintenance of the balance between pre-mRNA processing and mRNA export is of significant importance. However, how this balance is achieved remains largely unknown.U2 snRNP is a core component of the spliceosome. It is comprised of U2 snRNA, multisubunit SF3a and SF3b complexes, U2-snRNPspecific proteins A′ and B″, as well as the seven Sm proteins common to the spliceosomal snRNPs (8-10). During splicing, SF3b proteins contact the pre-mRNA at and near the branch site (BS) in a sequence-independent manner, stabilizing the U2 snRNA/BS interaction (11-18), and thereby regulate BS recognition and selection. Except for splicing, U2 snRNP also functions in the 3′ processing of polyadenylated and nonpolyadenylated mRNAs (19,20). On polyadenylated pre-mRNAs, U2 snRNP components including SF3b interact with the cleavage and polyadenylation specificity factor and enhance the rate of 3′ processing (19). On nonpolyadenylated histone pre-mRNAs, SF3b155, the largest SF3b subunit, together with Prp43, directly makes contact with the 7-nt motif, C/GAAGAAG, present in the coding region and facilitates 3′ processing as a component of U2 snRNP (20). To date, all known roles of SF3b are executed in the context of U2 snRNP, and whether it has a U2-snRNP-independent role remains unknown.The highly c...
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