Comella, P. | Search bioRxiv

bioRxiv2026

Dynamic 2'-O-Me of rRNA regulates ribosome translation in Arabidopsis nucleolin1 mutants and during seed-to-seedling transition

Across all kingdoms of life, 2'-O-ribose methylation (2'-O-Me) is the most abundant modification of ribosomal RNAs (rRNAs), which are central to ribosome assembly and function. The 2'-O-Me of specific rRNA sites is catalysed by C/D-box small nucleolar ribonucleoprotein (snoRNP) complexes. However, how and when the landscape of plant rRNA 2'-O-Me modifications is remodelled remains largely unexplored. To study the regulation of rRNA 2'-O-Me and its impact on ribosome translation, we characterised Arabidopsis NUCLEOLIN 1 (NUC1)-depleted plants, which exhibit reduced 2'-O-Me at dozens specific rRNA sites, and investigated the impact of 2'-O-Me in ribosome translation during plant development. We demonstrated that 2'-O-Me is dynamically regulated during seed-to-seedling transition. Our analysis identified differentially methylated rRNA sites, which are specifically located in structurally critical regions of the ribosome. Notably, this hypomethylation is uncoupled from the global expression, assembly, or subcellular localisation of C/D-box snoRNPs. We further observed that polysomes with low 2'-O-Me levels not only accumulate but also exhibit differential mRNA loading. These polysomes characterised by reduced 2'-O-Me at specific rRNA sites, influence multiples aspects of translation, including ribosomes stalling at the initiation, elongation and termination steps. Together, these findings advance our understanding of the dynamic regulation of rRNA 2'-O-methylation and its functional role in ribosome-mediated translation in plants.

plant biology↗

bioRxiv2025

A collection of patient-derived intestinal organoid lines reveals epithelial phenotypes associated with genetic drivers of pediatric inflammatory bowel disease

Pediatric Inflammatory Bowel Disease (IBD) is a chronic condition characterized by per-sistent intestinal inflammation in children and adolescents. Despite a rising global incidence, the underlying causes and optimal management strategies for pediatric IBD are still not fully understood. Compared to adult IBD, pediatric IBD frequently presents with distinct disease phenotypes, and is more commonly linked to rare monogenic variants that cause intestinal epithelial barrier dysfunction or affect the function of mucosal immune cells. While more than 100 genes have been associated with early-onset IBD, the roles of many of these genes in the intestinal epithelium and the mechanisms by which genetic variants contribute to disease remain poorly defined. Here we aimed to improve our understanding of intestinal epithelium dysfunction in early-onset IBD by conducting extensive molecular and cellular characterization to gain insights into patient-specific epithelial phenotypes and identify therapeutic targets. We generated intestinal epithelial organoids (IEOs) from 94 pediatric IBD patients, representing diverse clinical characteristics and including those with monogenic variants (BTK n=4, TTC7A n=3, IL10RA n=1, LRBA n=1, STXBP2 n=1, TTC37 n=1, TRNT1 n=1, PLCG2 n=1, DKC1 n=1, POLA1 n=1), and 46 non-IBD controls. This effort resulted in the largest RNA-seq dataset of pediatric IBD intestinal epithelial organoids to date, encompassing both baseline conditions and post-immunological stimulation, serving as a valuable resource for future research. We observed that IEOs effectively initiate inflammation upon stimulation with bacterial lysate, regardless of disease status, origin, or mutation status. Inflammatory stimulation triggered single-gene upregulation of IBD-linked SERPINA1 and LIFR across the IBD population compared to controls, suggesting their role in intestinal epithelial innate immune responses. However, co-expression network analysis showed no consistent transcriptional signatures across the entire IBD group at the systems level. Instead, differences emerged between controls and specific genotypes (TTC7A, STXBP2, LRBA), with STXBP2 and LRBA sharing an upregulated transcriptional response of IL-1 and SLC30-mediated zinc trafficking pathways. These findings underscore the potential of IEOs as a valuable model for studying IBD and offer key insights that could guide the development of targeted therapies for both monogenic and non-monogenic forms of IBD. O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/659052v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@10a4d9org.highwire.dtl.DTLVardef@b6cdadorg.highwire.dtl.DTLVardef@179216dorg.highwire.dtl.DTLVardef@181a4e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2018

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimers disease (AD) remains elusive. To elucidate its complex nature, we constructed multiscale causal network models on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene and protein expression into probabilistic causal models that enabled detection and prioritization of high-confidence key drivers of AD, including the top predicted key driver VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was achieved, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF versus controls. Our findings support a causal and/or protective role for VGF in AD pathogenesis and progression.\n\nOne sentence summaryVGF protects against Alzheimers disease

genomics↗