Cold Spring Harbor symposia on quantitative biology最新文献

Mammalian cells have many quality-control mechanisms that regulate protein-coding gene expression to ensure proper transcript synthesis, processing, and translation. Should a step in transcript metabolism fail to fulfill requisite spatial, temporal, or structural criteria, including the proper acquisition of RNA-binding proteins, then that step will halt, fail to proceed to the next step, and ultimately result in transcript degradation. Quality-control mechanisms constitute a continuum of processes that initiate in the nucleus and extend to the cytoplasm. Here, we present published and unpublished data for protein-coding genes whose expression is activated by the transcriptional coactivator PGC-1α. We show that PGC-1α movement from chromatin, to which it is recruited by DNA-binding proteins, to CBP80 at the 5' cap of nascent transcripts begins a series of co- and posttranscriptional quality- and quantity-control steps that, in total, ensure proper gene expression.

In fission yeast and plants, RNA-processing pathways contribute to heterochromatin silencing, complementing well-characterized pathways of transcriptional repression. However, it was unclear whether this additional level of regulation occurs in metazoans. In a genetic screen, we uncovered a pathway of silencing in Caenorhabditis elegans somatic cells, whereby the highly conserved, RNA-binding complex LSM2-8 contributes to the repression of heterochromatic reporters and endogenous genes bearing the Polycomb mark H3K27me3. Importantly, the LSM2-8 complex works cooperatively with a 5'-3' exoribonuclease, XRN-2, and disruption of the pathway leads to selective mRNA stabilization. LSM2-8 complex-mediated RNA degradation does not target nor depend on H3K9me2/me3, unlike previously described pathways of heterochromatic RNA degradation. Up-regulation of lsm-8-sensitive loci coincides with a localized drop in H3K27me3 levels in the lsm-8 mutant. Put into the context of epigenetic control of gene expression, it appears that targeted RNA degradation helps repress a subset of H3K27me3-marked genes, revealing an unappreciated layer of regulation for facultative heterochromatin in animals.

Eukaryotes deploy RNA-mediated gene silencing pathways to guard their genomes against selfish genetic elements, such as transposable elements and invading viruses. In plants, RNA-directed DNA methylation (RdDM) is used to silence selfish elements at the level of transcription. This process involves 24-nt short interfering RNAs (siRNAs) and longer noncoding RNAs to which the siRNAs base-pair. Recently, we showed that 24-nt siRNA biogenesis could be recapitulated in the test tube using purified enzymes, yielding biochemical answers to numerous questions left unresolved by prior genetic and genomic studies. Interestingly, each enzyme has activities that program what happens in the next step, thus channeling the RNAs within the RdDM pathway and restricting their diversion into alternative pathways. However, a similar mechanistic understanding is lacking for other important steps of the RdDM pathway. We discuss some of the steps most in need of biochemical investigation and important questions still in need of answers.

Long noncoding RNAs (lncRNAs) are gathering increasing attention toward their roles in different biological systems. In mammals, the richest repertoires of lncRNAs are expressed in the brain and in the testis, and the diversity of lncRNAs in the nervous system is thought to be related to the diversity and the complexity of its cell types. Supporting this notion, many lncRNAs are differentially expressed between different regions of the brain or in particular cell types, and many lncRNAs are dynamically expressed during embryonic or postnatal neurogenesis. Less is known about the functions of these genes, if any, but they are increasingly implicated in diverse processes in health and disease. Here, we review the current knowledge about the roles and importance of lncRNAs in the central and peripheral nervous systems and discuss the specific niches within gene regulatory networks that might be preferentially occupied by lncRNAs.