Cold Spring Harbor symposia on quantitative biology最新文献

Long noncoding RNAs (lncRNAs) are fundamental regulators of various cellular processes. A subset of lncRNAs, termed architectural RNAs (arcRNAs), function in the formation and maintenance of phase-separated membraneless organelles in multiple eukaryotic species. These membraneless organelles represent an important type of compartmentalization in the crowded cellular environment and have several distinct features. The NEAT1_2 lncRNA is a well-characterized arcRNA that functions as an essential scaffold of paraspeckle nuclear bodies. Here, we describe the biogenesis of paraspeckles on arcRNAs through phase separation, focusing on the specific functions of multiple NEAT1_2 RNA domains and their partner RNA-binding proteins. Finally, we present an updated model of paraspeckle formation and discuss future perspectives of research into arcRNA-instructed architectures of phase-separated nuclear bodies.

Messenger RNAs (mRNAs) are the templates for protein synthesis as the coding region is translated into the amino acid sequence. mRNAs also contain 3' untranslated regions (3' UTRs) that harbor additional elements for the regulation of protein function. If the amino acid sequence of a protein is necessary and sufficient for its function, we call it 3' UTR-independent. In contrast, functions that are accomplished by protein complexes whose formation requires the presence of a specific 3' UTR are 3' UTR-dependent protein functions. We showed that 3' UTRs can regulate protein activity without affecting protein abundance, and alternative 3' UTRs can diversify protein functions. We currently think that the regulation of protein function by 3' UTRs is facilitated by the local environment at the site of protein synthesis, which we call the nurturing niche for nascent proteins. This niche is composed of the mRNA and the bound proteins that consist of RNA-binding proteins and recruited proteins. It enables the formation of specific protein complexes, as was shown for TIS granules, a recently discovered cytoplasmic membraneless organelle. This finding suggests that changing the niche for nascent proteins will alter protein activity and function, implying that cytoplasmic membraneless organelles can regulate protein function in a manner that is independent of protein abundance.

Eukaryotic gene expression requires the cumulative activity of multiple molecular machines to synthesize and process newly transcribed pre-messenger RNA. Introns, the noncoding regions in pre-mRNA, must be removed by the spliceosome, which assembles on the pre-mRNA as it is transcribed by RNA polymerase II (Pol II). The assembly and activity of the spliceosome can be modulated by features including the speed of transcription elongation, chromatin, post-translational modifications of Pol II and histone tails, and other RNA processing events like 5'-end capping. Here, we review recent work that has revealed cooperation and coordination among co-transcriptional processing events and speculate on new avenues of research. We anticipate new mechanistic insights capable of unraveling the relative contribution of coupled processing to gene expression.

This summary of the 84th Cold Spring Harbor Laboratory (CSHL) Symposium on Quantitative Biology: RNA Control and Regulation, held in May 2019, highlights key emerging themes in this field, which now impacts nearly every aspect of biology and medicine. Recent discoveries accelerated by technological developments reveal enormous diversity of RNAs and RNA-binding proteins (RBPs) with ever-increasing roles in eukaryotes. Atomic structures and live-cell imaging of transcription, RNA splicing, 3'-end processing, modifications, and degradation machineries provide mechanistic insights, explaining hundreds of diseases caused by their perturbations. This great progress uncovered numerous targets for therapies, some of which have already been successfully exploited, and many opportunities for pharmacological intervention and RNA-guided genome engineering. Myriad unexplained RNAs and RBPs leave the RNA field open for many more exciting discoveries.

A complex network of RNA transcripts is generated from eukaryotic genomes, many of which are processed in unexpected ways. Here, we highlight how premature transcription termination events at protein-coding gene loci can simultaneously lead to the generation of short RNAs and attenuate production of full-length mRNA transcripts. We recently showed that the Integrator (Int) complex can be selectively recruited to protein-coding gene loci, including Drosophila metallothionein A (MtnA), where the IntS11 RNA endonuclease cleaves nascent transcripts near their 5' ends. Such premature termination events catalyzed by Integrator can repress the expression of some full-length mRNAs by more than 100-fold. Transcription at small nuclear RNA (snRNA) loci is likewise terminated by Integrator cleavage, but protein-coding and snRNA gene loci have notably distinct dependencies on Integrator subunits. Additional mechanisms that attenuate eukaryotic gene outputs via premature termination have been discovered, including by the cleavage and polyadenylation machinery in a manner controlled by U1 snRNP. These mechanisms appear to function broadly across the transcriptome. This suggests that synthesis of full-length transcripts is not always the default option and that premature termination events can lead to a variety of transcripts, some of which may have important and unexpected biological functions.

The nucleus accumbens (NAc) is a key node of the brain's circuitry that is responsible for translating motivation into action. It has been implicated in playing critical roles in virtually all forms of adaptive and pathological motivated behaviors. It is subject to modulation by a broad array of inputs that influence NAc activity in complex ways that are still poorly understood. Here, we briefly review current knowledge about the behavioral consequences of NAc modulation, focusing on recent studies that use novel techniques developed and implemented over the last decade.