Biology subjects

Lubelsky, Y.

Publications and source records attributed to Lubelsky, Y..

4 recordsLinked to original sources

bioRxiv2025

Inducible formation of fusion transcripts upregulates haploinsufficient CHD2 gene expression

Modes of action of long noncoding RNAs (lncRNAs) are poorly understood. CHASERR is a broadly expressed lncRNA located immediately upstream of the promoter of the CHD2 gene. We show that antisense oligonucleotides (ASOs) targeting conserved motifs in CHASERRs last exon induce the formation of a fusion transcript joining CHASERR to CHD2. This fusion transcript is exported to the cytoplasm and translated into full-length CHD2 protein. Deleting the same motifs in mice mimics the ASO effect, increasing CHD2 protein without causing the deleterious effects associated with full CHASERR ablation. The fusion transcripts are also expressed endogenously, induced in activated neurons, and their constitutive induction affects neuronal gene expression and chromatin accessibility. Perinatal introduction of the ASO into Chd2+/- mice up-regulates CHD2 expression and alleviates behavioral phenotypes caused by CHD2 haploinsufficiency, providing a therapeutic route to CHD2 haploinsufficiency. This concept of targeting upstream genes with ASOs to induce transcript fusion can be extended to other gene pairs, and is thus a broadly relevant approach for increasing haploinsufficient gene expression.

molecular biology↗

bioRxiv2020

SARS-CoV-2 utilizes a multipronged strategy to suppress host protein synthesis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. Here, we use RNA-sequencing and ribosome profiling along SARS-CoV-2 infection and comprehensively define the mechanisms that are utilized by SARS-CoV-2 to shutoff cellular protein synthesis. We show SARS-CoV-2 infection leads to a global reduction in translation but that viral transcripts are not preferentially translated. Instead, we reveal that infection leads to accelerated degradation of cytosolic cellular mRNAs which facilitates viral takeover of the mRNA pool in infected cells. Moreover, we show that the translation of transcripts whose expression is induced in response to infection, including innate immune genes, is impaired, implying infection prevents newly transcribed cellular mRNAs from accessing the ribosomes. Overall, our results uncover the multipronged strategy employed by SARS-CoV-2 to commandeer the translation machinery and to suppress host defenses.

microbiology↗

bioRxiv2018

Recruitment of the protein phosphatase-1 catalytic subunit to promoters by the dual-function transcription factor RFX1

SummeryRFX proteins are a family of conserved DNA binding proteins involved in various, essential cellular and developmental processes. RFX1 is a ubiquitously expressed, dual-activity transcription factor capable of both activation and repression of target genes.\n\nThe exact mechanism by which RFX1 regulates its target is not known yet. In this work, we show that the C-terminal repression domain of RFX1 interacts with the Serine/Threonine protein phosphatase PP1c, and that interaction with RFX1 can target PP1c to specific sites in the genome. Given that PP1c was shown to de-phosphorylate several transcription factors, as well as the regulatory C-terminal domain of RNA Polymerase II the recruitment of PP1c to promoters may be a mechanism by which RFX1 regulates the target genes.

molecular biology↗

bioRxiv2017

Sequences enriched in Alu repeats drive nuclear localization of long RNAs in human cells

Long noncoding RNAs (lncRNAs) are emerging as key players in multiple cellular pathways, but their modes of action, and how those are dictated by sequence remain elusive. While lncRNAs share most molecular properties with mRNAs, they are more likely to be enriched in the nucleus, a feature that is likely to be crucial for function of many lncRNAs, but whose molecular underpinnings remain largely unclear. In order identify elements that can force nuclear localization we screened libraries of short fragments tiled across nuclear RNAs, which were cloned into the untranslated regions of an efficiently exported mRNA. The screen identified a short sequence derived from Alu elements and found in many mRNAs and lncRNAs that increases nuclear accumulation and reduces overall expression levels. Measurements of the contribution of individual bases and short motifs to the element functionality identified a combination of RCCTCCC motifs that are bound by the abundant nuclear protein HNRNPK. Increased HNRNPK binding and C-rich motifs are predictive of substantial nuclear enrichment in both lncRNAs and mRNAs, and this mechanism is conserved across species. Our results thus detail a novel pathway for regulation of RNA accumulation and subcellular localization that has been co-opted to regulate the fate of transcripts that integrated Alu elements.

molecular biology↗