Biology subjects

Rachez, C.

Publications and source records attributed to Rachez, C..

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↗

bioRxiv2021

Alu repeats at the boundaries of regulatory elements shape the epigenetic environment of immune genes in T cells

Promoters and enhancers are sites of transcription initiation (TSSs) and carry active histone modifications, including H3K4me1, H3K4me3, and H3K27ac. Yet, the principles governing the boundaries of such regulatory elements are still poorly characterized. Alu elements are good candidates for a boundary function, being highly abundant in gene-rich regions, while essentially excluded from regulatory elements. Here, we show that the interval from the TSS to the first upstream Alu accommodates all H3K4me3 and most H3K27ac marks, while excluding DNA methylation. Remarkably, the average length of this intervals greatly varies in-between tissues, being longer in stem-and shorter in immune-cells. The very shortest TSS-to-Alu intervals were observed at promoters active in T cells, particularly at immune genes, correlating with RNA polymerase II transcription through the first Alu and accumulation of H3K4me1 signal on this first Alu. Finally, DNA methylation at first-Alus was found to evolved with age, regressing from young to middle-aged, then recovering later in life. Thus, the first Alus upstream of TSSs appear as dynamic boundaries marking the transition from DNA methylation to active histone modifications at regulatory elements, while also participating in the recording of immune gene transcriptional events by positioning H3K4me1-modified nucleosomes.

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↗