Biology subjects

Costallat, M.

Publications and source records attributed to Costallat, M..

3 recordsLinked to original sources

bioRxiv2023

Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis

HP1/CBX5 is an epigenetic regulator with a suspected role in multiple sclerosis (MS). Here, using high-depth RNA sequencing on monocytes, we identified a subset of MS patients with reduced CBX5 expression, correlating with progressive stages of the disease and extensive transcriptomic alterations. Examination of rare non-coding RNA species in these patients revealed impaired maturation/degradation of U snRNAs and enhancer-RNAs, indicative of a reduced activity of the Integrator, a complex with suspected links to increased MS risk. At protein-coding genes, compromised Integrator activity manifested in reduced pre-mRNA splicing efficiency and altered expression of genes regulated by RNA polymerase II pause-release. Inactivation of Cbx5 in the mouse mirrored most of these transcriptional defects and resulted in hypersensitivity to Experimental Autoimmune Encephalomyelitis (EAE). Collectively, our observations suggested a major contribution of the Integrator complex in safeguarding against transcriptional anomalies characteristic of MS, with HP1/CBX5 emerging as an unexpected regulator of this complexs activity. These findings bring novel insights into the transcriptional aspects of MS and provide potential new criteria in patient stratification.

genomics↗

bioRxiv2019

Reduced RNA turnover as a driver of cellular senescence

Accumulation of senescent cells is an important contributor to chronic inflammation upon aging. While cytoplasmic DNA was shown to drive the inflammatory phenotype of senescent cells, an equivalent role for RNA has never been explored. Here, we show that some senescent cells accumulate long promoter RNAs and 3 gene extensions, rich in retrotransposon sequences. Accordingly, these cells display increased expression of genes involved in detecting double stranded RNA of viral origin downstream of the interferon pathway. The RNA accumulation is correlated with signs of reduced RNA turn-over, including in some cases, reduced expression of RNA exosome subunits. Reciprocally, engineered inactivation of RNA exosome subunit Exosc3 induces expression of multiple senescence markers. A senescence-like RNA accumulation is also observed in cells exposed to oxidative stress, an important trigger of cellular senescence. Altogether, we propose that in a subset of senescent cells, repeat-containing transcripts stabilized by oxidative stress or reduced RNA exosome activity participate, possibly in combination with cytoplasmic DNA, in driving and maintaining the permanent inflammatory state characterizing cellular senescence.

molecular biology↗

bioRxiv2019

An impact of HP1γ on the fidelity of pre-mRNA splicing arises from its ability to bind RNA via intronic repeated sequences.

HP1 proteins are best known as markers of heterochromatin and gene silencing. Yet, they are also RNA-binding proteins and the HP1{gamma}/Cbx3 family member is present on transcribed genes together with RNA polymerase II, where it regulates co-transcriptional processes such as alternative splicing. To gain insight in the role of the RNA binding activity of HP1{gamma} in transcriptionally active chromatin, we have captured and analyzed RNAs associated with this protein. We find that HP1{gamma} specifically recognizes hexameric RNA motifs and coincidentally transposable elements of the SINE family. As these elements are abundant in introns, while essentially absent from exons, the HP1{gamma} RNA binding activity tethers unspliced pre-mRNA to chromatin via the intronic region and limits the usage of intronic cryptic splice sites. Thus, our data unveil novel determinants in the relationship between chromatin and co-transcriptional splicing.

molecular biology↗