Biology subjects

Matthews, A. M.

Publications and source records attributed to Matthews, A. M..

5 recordsLinked to original sources

bioRxiv2026

Structure-guided antisense-oligonucleotides selectively modulate frameshifting of a human gene

Programmed -1 ribosomal frameshifting (-1 PRF) is a conserved translational recoding mechanism that expands proteomic diversity and regulates gene expression through RNA structural elements, most notably stimulatory pseudoknots. This mechanism is common in viruses, where it is used to control stoichiometry of viral protein products generated by the host cell to direct viral replication. Despite its biological importance, strategies to selectively modulate frameshifting remain limited. The mammalian retrotransposon-derived gene PEG10 also relies on -1 PRF to produce a fusion protein, gag-pol, which is necessary for reproduction but has also been implicated in neurological diseases. Here, we establish an antisense oligonucleotide (ASO) targeting an RNA structural element as an effective approach to tune PEG10 frameshifting. Using structure prediction, systematic antisense tiling across the PEG10 pseudoknot, and multiple model systems, we identify a discrete functional hotspot within the lower RNA stem that governs frameshift efficiency. ASOs targeting this region selectively suppress gag-pol production with minimal impact on gag, thereby shifting the ratio of protein products in a dose-dependent manner. Mechanistic dissection using RNase H-active and -inactive ASO designs, pre-annealed duplexes, and fluorescence-based subcellular localization supports a predominantly nuclear mode of action in which ASOs engage nascent PEG10 transcripts and bias pseudoknot folding away from the frameshift-competent conformation. Functional effects are conserved between human cell lines and murine models, including neurons, highlighting the generality of this strategy. Together, our results define RNA structural dynamics as a druggable layer of translational regulation and establish antisense modulation of pseudoknot folding as a way to control endogenous frameshifting. This work provides a conceptual and practical framework for targeting recoding-dependent gene products such as PEG10 in disease and suggests broader applicability of structure-directed ASOs to viral and cellular frameshifting elements.

biochemistry↗

bioRxiv2026

The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons

Abstract/SummaryRetroelements, including retrotransposons, endogenous retroviruses, and their fragments, as well as rare co-opted or domesticated retroelements, can contribute to neurodegenerative disorders and aging through modulation of gene expression and induction of neuroinflammation. Paternally Expressed Gene 10 (PEG10) is a retroelement-derived human gene that has recently been identified as a putative driver of Amyotrophic Lateral Sclerosis (ALS) and Angelmans Syndrome. PEG10 has been reported to bind nucleic acid and undergoes a complex self-processing pathway that results in gene expression changes when the protein accumulates in cells. Here, we report that PEG10 has selectivity for binding U/G-rich RNAs and influences widespread gene expression changes. PEG10 overexpression mimics the loss of TDP-43 in broad changes to gene expression, including dysregulation of mRNA splicing pathways. Specific changes to mRNA splicing were largely unique between TDP-43 knockdown and PEG10 overexpression, as classic TDP-43 targets including STMN2 were not altered by PEG10. Instead, we identified a unique role for PEG10 in regulating splicing of neuregulin 3 (NRG3), a ligand for the neuronal receptor ERBB4. In SH-SY5Y cells and in human neurons overexpressing PEG10, NRG3 protein levels were decreased along cellular processes, suggesting that these cells are less competent at signaling through the NRG3/ERBB4 axis. Using human patient data, we observed similar changes to NRG3 splicing in UBQLN2-mediated ALS, where PEG10 is accumulated, as well as in some cases of sporadic ALS. In conclusion, the retroelement-derived gene PEG10 plays an unexpected role in regulating splicing of neuronal transcripts, which mimics some of the transcript changes observed in human ALS patient samples. Ultimately, this work has implications for the study of PEG10, and mRNA splicing in neurological diseases associated with elevated PEG10 abundance. HighlightsO_LIPEG10 NC expression influences abundance of transcripts implicated in ALS C_LIO_LIPEG10 NC expression leads to an exon skipping event in neuregulin 3 (NRG3) C_LIO_LINRG3 expression is decreased along dendrites of PEG10 NC expressing human neurons C_LIO_LIExpression of PEG10 NC mimics changes observed in human ALS C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/727000v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1a957d2org.highwire.dtl.DTLVardef@c4b15corg.highwire.dtl.DTLVardef@15825faorg.highwire.dtl.DTLVardef@25533d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

The BirdsPlus Index, a novel method for assessing site-level conservation values.

While there is growing interest in sustainable management practices to mitigate the biodiversity impacts of agriculture, logging, and other critical societal needs, implementation of such practices is often hindered by a lack of cost-effective, fine-scale metrics that directly link management actions to conservation outcomes. We introduce the BirdsPlus Index (BPI), a novel, scalable approach that integrates monitoring data, remote sensing, and conservation-weighted species scores to quantify deviations of observed site scores from spatiotemporally explicit expectations. Using nearly 29,000 recordings from the Macaulay Library, we generated acoustic checklists with the Merlin and BirdNET sound identification models under multiple detection thresholds. We matched these acoustic checklists with species-specific conservation values (BirdsPlus species scores), then trained random forest models to predict total, site-level biodiversity (the sum of these species scores) given environmental and effort covariates. The resulting model also enabled us to map expected BirdsPlus site scores across the landscape. These scores integrate information on species conservation status, ecological roles, and phylogenetic and functional uniqueness. BPI was calculated as the residual between observed and expected site scores, thereby providing a direct site-level measure of conservation value. Across 30 sites, we found that BPI values were consistent across acoustic models and detection thresholds, with high-scoring sites supporting regionally uncommon breeders and habitat specialists. While acoustic- and observer-based (eBird) models showed differing spatial patterns, both aligned with known ecological drivers such as urban density, elevation, and wetland cover. Our results demonstrate that acoustic checklists can be used to model expected biodiversity over time and space, and that the BPI provides a robust, interpretable metric for evaluating the ecological integrity of local sites. Beyond its immediate application to conservation planning, this framework lays the foundation for global, real-time biodiversity monitoring that leverages automated acoustic classifiers, citizen science, and remote sensing to integrate conservation value into development and management decisions.

ecology↗

bioRxiv2025

Aligning conservation status, vulnerability factors, and ecological and evolutionary uniqueness to produce integrated assessments of the world's birds

A growing awareness, now enshrined in the Kunming-Montreal Global Biodiversity Framework, of the need to monitor biodiversity effectively at scale has led to a proliferation of novel solutions for doing so. Although global biodiversity encompasses all life, from tiny nitrogen-fixing bacteria to emergent rainforest trees, birds have several characteristics that make them a frequent focus of such monitoring efforts. In particular, birds frequently give diagnostic, species-specific vocalizations that simplify monitoring, they perform a number of critical ecosystem services, they are widely distributed in most ecosystems with strong representation on all continents, and the basic ecology, conservation status, populations, and distributions of many species is well known; birds thus provide a window into the underlying health and habitats of the systems under study. How best to summarize biodiversity monitoring results is a research question that has led to the development of approaches that incorporate species IUCN Red List threat assessments into site-level biodiversity scores. Notably, birds vocal behavior means that they can be effectively surveyed at scale with passive acoustic monitoring, and the potential to link such monitoring with automated identification and therefore quickly generate site-level biodiversity scores is an appealing approach to implement rigorous evaluations of global biodiversity. Yet, while many of the worlds birds are suffering worrisome population declines, the vast majority of species (78%) are still ranked "Least Concern" by the Red List. In an effort to develop a species scoring system that would be more conducive to such site-level valuations, we integrated key databases of species population status assessments, exposure to known vulnerability factors, and their functional and phylogenetic uniqueness to provide quantitative summaries of their conservation significance. We augmented these databases with two novel data sets available for most of the worlds birds: quantitative measurements of migration distances, and species-level phylogenetic and functional uniqueness values comparing each species to those it co-occurs with throughout its range. While the resulting BirdsPlus species scores also inherently reflect our own scientific expertise and judgement, our approach is transparent, dynamic, easily updated, and readily modified by users with different goals or values.

ecology↗

bioRxiv2021

A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta

BackgroundHuman placental DNA methylation (DNAme) data is a valuable resource for studying sex differences during gestation, as DNAme profiles after delivery reflect the cumulative effects of gene expression patterns and exposures across gestation. Here, we present an analysis of sex differences in autosomal patterns of DNAme in the uncomplicated term placenta (n=343) using the Illumina 450K array. ResultsUsing a false discovery rate < 0.05 and a mean sex difference in DNAme beta value of > 0.10, we identified 162 autosomal CpG sites that were differentially methylated by sex, and that replicated in an independent cohort of samples (n=293). Several of these differentially methylated CpG sites were part of larger correlated regions of differential DNAme, and many also exhibited sex-specific DNAme variability. Although global DNAme levels did not differ by sex, the majority of significantly differentially methylated CpGs were more highly methylated in male placentae, the opposite of what is seen in differential methylation analyses of somatic tissues. Interestingly, patterns of autosomal DNAme at these significantly differentially methylated CpGs organized placental samples along a continuum, rather than into discrete male and female clusters, and sample position along the continuum was significantly associated with maternal age and newborn birthweight standard deviation. ConclusionsOur results provide a comprehensive analysis of sex differences in autosomal DNAme in the term human placenta. We report a list of high-confidence autosomal sex-associated differentially methylated CpGs, and identify several key features of these loci that suggest their relevance to sex differences observed in normative and complicated pregnancies.

genomics↗