Bezerra, O. C. L. | bioRxiv Science

bioRxiv2026

Detecting DNA methylation patterns suggestive of variable escape from X-chromosome inactivation

The X chromosome is often excluded from studies analyzing associations between traits and DNA methylation. In females, one copy of most genes on the X is inactivated (X-chromosome inactivation; XCI) through DNA methylation of the gene promoter on the inactive X. This leads to challenges in analyzing and interpreting DNA methylation data patterns. Particularly for sex-biased diseases and traits, there may be many loci of interest on the X chromosome, which contains about 5% of the genome. To address the need for appropriate analysis of DNA methylation data on the X chromosome, we develop a statistical approach to infer locus-specific escape from XCI sensitive to phenotype or covariate values. Performance of this method is illustrated by analysis of data from two sex-biased traits: rheumatoid arthritis which is 3-fold more common in females, and recurrent venous thromboembolism which occurs 2.5 times more often in males. Analyses of these two datasets identify new trait-associated loci on the X chromosome, demonstrate the capabilities of the new method for both bisulfite sequencing data and Illumina EPIC data, suggest at least one locus where variable escape may explain a sex-specific disease association, and rule out variable escape as a potential explanation at other loci. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/732395v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@108c23aorg.highwire.dtl.DTLVardef@77dc0org.highwire.dtl.DTLVardef@1d105d0org.highwire.dtl.DTLVardef@1d4b543_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender (bioRender.com)

genomics↗

bioRxiv2019

Liquid-liquid phase separation and aggregation of the prion protein globular domain modulated by a high-affinity DNA aptamer

Structural conversion of cellular prion protein (PrPC) into scrapie PrP (PrPSc) and subsequent aggregation are key events for the onset of Transmissible Spongiform Encephalopathies (TSEs). Experimental evidences support the role of nucleic acids (NAs) in assisting the protein conversion process. Here, we used the SELEX methodology to identify two 25-mer DNA aptamers against the globular domain of recombinant murine PrP (rPrP90-231), namely A1 and A2. High-affinity binding of A1 and A2 to rPrP was verified by ITC. Aptamers structure was characterized by theoretical predictions, CD, NMR and SAXS, revealing that A1 adopts a hairpin conformation. Aptamer binding caused dynamic aggregation of rPrP90-231, resulting from the ability of rPrP90-231 to undergo liquid-liquid phase separation (LLPS). While free rPrP90-231 phase separated into large droplets, aptamer binding increased the amount but reduced the size of the condensates. Strikingly, a modified A1 aptamer that does not adopt a hairpin structure induced transition to an ordered state, suggestive of amyloid formation on the surface of the droplets. Our results describe for the first time PrP:NA interaction leading to LLPS and modulation of this effect depending on NA structure and binding stoichiometry, shedding light on the role of NAs in PrP misfolding and TSEs.

biophysics↗