Directory
2019
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System-wide Profiling of RNA-Binding Proteins Uncovers Key Regulators of Virus Infection.
- Journal : Mol Cell
- 2019
- The compendium of RNA-binding proteins (RBPs) has been greatly expanded by the development of RNA-interactome capture (RIC). However, it remained unknown if the complement of RBPs changes in response to environmental perturbations and whether these rearrangements are important. To answer these questions, we developed "comparative RIC" and applied it to cells challenged with an RNA virus called sindbis (SINV). Over 200 RBPs display differential interaction with RNA upon SINV infection. These alterations are mainly driven by the loss of cellular mRNAs andthe emergence of viral RNA. RBPs stimulated by the infection redistribute to viral replication factories and regulate the capacity of the virus to infect. For example, ablation of XRN1 causes cells to be refractory to SINV, while GEMIN5 moonlights as a regulator of SINV gene expression. In summary, RNA availability controls RBP localization and function in SINV-infected cells.
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TCTP and CSN4 control cell cycle progression and development by regulating CULLIN1 neddylation in plants and animals.
- Journal : PLoS Genet
- 2019
- Translationally Controlled Tumor Protein (TCTP) controls growth by regulating theG1/S transition during cell cycle progression. Our genetic interaction studies showthat TCTP fulfills this role by interacting with CSN4, a subunit of the COP9Signalosome complex, known to influence CULLIN-RING ubiquitin ligases activity bycontrolling CULLIN (CUL) neddylation status. In agreement with these data,downregulation of CSN4 in Arabidopsis and in tobacco cells leads to delayed G1/Stransition comparable to that observed when TCTP is downregulated. Loss-of-functionof AtTCTP leads to increased fraction of deneddylated CUL1, suggesting that AtTCTPinterferes negatively with COP9 function. Similar defects in cell proliferation andCUL1 neddylation status were observed in Drosophila knockdown for dCSN4 or dTCTP,respectively, demonstrating a conserved mechanism between plants and animals.Together, our data show that CSN4 is the missing factor linking TCTP to the controlof cell cycle progression and cell proliferation during organ development and openperspectives towards understanding TCTP's role in organ development and disordersassociated with TCTP miss-expression.
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The extruded non-template strand determines the architecture of R-loops.
- Journal : Nucleic Acids Res
- 2019
- Three-stranded R-loop structures have been associated with genomic instability phenotypes. What underlies their wide-ranging effects on genome stability remains poorly understood. Here we combined biochemical and atomic force microscopy approaches with single molecule R-loop footprinting to demonstrate that R-loops formed at the model Airn locus in vitro adopt a defined set of three-dimensionalconformations characterized by distinct shapes and volumes, which we call R-loopobjects. Interestingly, we show that these R-loop objects impose specific physical constraints on the DNA, as revealed by the presence of stereotypical angles in the surrounding DNA. Biochemical probing and mutagenesis experiments revealed that the formation of R-loop objects at Airn is dictated by the extruded non-template strand, suggesting that R-loops possess intrinsic sequence-driven properties. Consistent with this, we show that R-loops formed at the fission yeast gene sum3 do not form detectable R-loop objects. Our results reveal that R-loops differ by their architectures and that the organization of the non-template strand is a fundamental characteristic of R-loops, which could explain that only a subset of R-loops is associated with replication-dependent DNA breaks.
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The long noncoding RNA CHROME regulates cholesterol homeostasis in primate.
- Journal : Nat Metab
- 2019
- The human genome encodes thousands of long non-coding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, that regulates cellular andsystemic cholesterol homeostasis. LncRNA CHROME expression is influenced by dietary and cellular cholesterol via the sterol-activated liver X receptor transcription factors, which control genes mediating responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and HDL biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. CHROME knockdown in human hepatocytes and macrophages increases levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing expression of their overlapping target gene networks and associated biologic functions. In particular, cells lacking CHROME show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify CHROME as a central component of the non-coding RNA circuitry controlling cholesterol homeostasis in humans.
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WASABI: a dynamic iterative framework for gene regulatory network inference
- Journal : BMC Bioinformatics
- 2019
Link to PubMed entry