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Selskabet for Trykkefrihedens rette Brug og folkeoplysningen Selskabet for Trykkefrihedens rette Brug blev stiftet i marts 1835. Det var den første politiske forening efter århundredeskiftet. Selskabet udsprang af et initiativ fra en gruppe embedsmænd, borgere og småborgere, der gennem en petition anmodede kongen om ikke at skærpe censuren. Baggrunden var, at pressen i begyndelsen af 1830rne havde kritiseret trykkefrihedslovgivningen og andre politiske forhold.Selskabet for Trykkefrihedens rette Brug og folkeoplysningen Selskabet for Trykkefrihedens rette Brug blev stiftet i marts 1835. Det var den første politiske forening efter århundredeskiftet. Selskabet udsprang af et initiativ fra en gruppe embedsmænd, borgere og småborgere, der gennem en petition anmodede kongen om ikke at skærpe censuren. Baggrunden var, at pressen i begyndelsen af 1830rne havde kritiseret trykkefrihedslovgivningen og andre politiske forhold

Activating RNAs associate with Mediator to enhance chromatin architecture and transcription

Recent advances in genomic research have revealed the existence of a large number of transcripts devoid of protein-coding potential in multiple organisms. Although the functional role for long non-coding RNAs (lncRNAs) has been best defined in epigenetic phenomena such as X-chromosome inactivation and imprinting, different classes of lncRNAs may have varied biological functions. We and others have identified a class of lncRNAs, termed ncRNA-activating (ncRNA-a), that function to activate their neighbouring genes using a cis-mediated mechanism. To define the precise mode by which such enhancer-like RNAs function, we depleted factors with known roles in transcriptional activation and assessed their role in RNA-dependent activation. Here we report that depletion of the components of the co-activator complex, Mediator, specifically and potently diminished the ncRNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo, Mediator is recruited to ncRNA-a target genes and regulates their expression. We show that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine 10. The Mediator complex harbouring disease- displays diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the two loci. Our results identify the human Mediator complex as the transducer of activating ncRNAs and highlight the importance of Mediator and activating ncRNA association in human disease

Long Noncoding RNAs Usher In a New Era in the Biology of Enhancers

Enhancer-associated long noncoding RNAs act over long distances and across chromosomes to activate transcription at distal promoters. Here, we address the latest advances made toward understanding the role of long noncoding RNA expression and the involvement of these RNAs in enhancer function through association with protein factors and modulation of chromatin structure

PROmiRNA: a new miRNA promoter recognition method uncovers the complex regulation of intronic miRNAs

The regulation of intragenic miRNAs by their own intronic promoters is one of the open problems of miRNA biogenesis. Here, we describe PROmiRNA, a new approach for miRNA promoter annotation based on a semi-supervised statistical model trained on deepCAGE data and sequence features. We validate our results with existing annotation, PolII occupancy data and read coverage from RNA-seq data. Compared to previous methods PROmiRNA increases the detection rate of intronic promoters by 30%, allowing us to perform a large-scale analysis of their genomic features, as well as elucidate their contribution to tissue-specific regulation. PROmiRNA can be downloaded from http://promirna.molgen.mpg.de

A long non-coding RNA links calreticulin-mediated immunogenic cell removal to RB1 transcription

A subset of promoters bidirectionally expresses long non-coding RNAs (ncRNAs) of unknown function and protein-coding genes (PCGs) in parallel. Here, we define a set of 1107 highly conserved human bidirectional promoters that mediate the linked expression of long ncRNAs and PCGs. Depletion of the long ncRNA expressed from the RB1 promoter, ncRNA-RB1, reveals regulatory effects different from the RB1-controlled transcriptional program. ncRNA-RB1 positively regulates the expression of calreticulin (CALR) that in response to certain therapeutic interventions can translocate from the endoplasmic reticulum to the cell surface, hence activating anticancer immune responses. Knockdown of ncRNA-RB1 in tumor cells reduced expression of CALR, impaired the translocation of the protein to the cell surface upon treatment with anthracylines and consequently inhibited the cellular uptake by macrophages. In conclusion, co-transcription of ncRNA-RB1 and RB1 provides a positive link between the expression of the two tumor suppressors RB1 and the immune-relevant CALR protein. This regulatory interplay exemplifies disease-relevant co-regulation of two distinct gene products, in which loss of expression of one oncosuppressor protein entails the abolition of additional tumor-inhibitory mechanisms

Altered m6A RNA methylation contributes to hippocampal memory deficits in Huntington's disease mice.

N6-methyladenosine (m6A) regulates many aspects of RNA metabolism and is involved in learning and memory processes. Yet, the impact of a dysregulation of post-transcriptional m6A editing on synaptic impairments in neurodegenerative disorders remains unknown. Here we investigated the m6A methylation pattern in the hippocampus of Huntington's disease (HD) mice and the potential role of the m6A RNA modification in HD cognitive symptomatology. m6A modifications were evaluated in HD mice subjected to a hippocampal cognitive training task through m6A immunoprecipitation sequencing (MeRIP-seq) and the relative levels of m6A-modifying proteins (FTO and METTL14) by subcellular fractionation and Western blot analysis. Stereotaxic CA1 hippocampal delivery of AAV-shFTO was performed to investigate the effect of RNA m6A dysregulation in HD memory deficits. Our results reveal a m6A hypermethylation in relevant HD and synaptic related genes in the hippocampal transcriptome of Hdh+/Q111 mice. Conversely, m6A is aberrantly regulated in an experience-dependent manner in the HD hippocampus leading to demethylation of important components of synapse organization. Notably, the levels of RNA demethylase (FTO) and methyltransferase (METTL14) were modulated after training in the hippocampus of WT mice but not in Hdh+/Q111 mice. Finally, inhibition of FTO expression in the hippocampal CA1 region restored memory disturbances in symptomatic Hdh+/Q111 mice. Altogether, our results suggest that a differential RNA methylation landscape contributes to HD cognitive symptoms and uncover a role of m6A as a novel hallmark of HD

Identification of a long non-coding RNA-associated RNP complex regulating metastasis at the translational step

Long non-coding RNAs (lncRNAs) are a novel class of regulatory genes that play critical roles in various processes ranging from normal development to human diseases such as cancer progression. Recent studies have shown that lncRNAs regulate the gene expression by chromatin remodelling, transcription, splicing and RNA decay control, enhancer function, and epigenetic regulation. However, little is known about translation regulation by lncRNAs. We identified a translational regulatory lncRNA (treRNA) through genome-wide computational analysis. We found that treRNA is upregulated in paired clinical breast cancer primary and lymph-node metastasis samples, and that its expression stimulates tumour invasion in vitro and metastasis in vivo. Interestingly, we found that treRNA downregulates the expression of the epithelial marker E-cadherin by suppressing the translation of its mRNA. We identified a novel ribonucleoprotein (RNP) complex, consisting of RNA-binding proteins (hnRNP K, FXR1, and FXR2), PUF60 and SF3B3, that is required for this treRNA functions. Translational suppression by treRNA is dependent on the 3'UTR of the E-cadherin mRNA. Taken together, our study indicates a novel mechanism of gene regulation by lncRNAs in cancer progression