Biology subjects

Lopes, E.

Publications and source records attributed to Lopes, E..

5 recordsLinked to original sources

bioRxiv2024

Incorporating histone H2B variants into chromatin modifies chromatin accessibility to induce epithelial to mesenchymal transition in breast cancer

Histones scaffold genomic DNA and regulate access to the transcriptional machinery. However, naturally occurring histone variants can alter histone-DNA interactions, DNA and histone modifications, and the chromatin interactome. Hence, alterations in histone variant deposition can disrupt chromatin, and are increasingly recognized as a way to trigger various disease, including cancer. While significant attention has been placed on the biochemical and functional roles of H2A, H3, and H4 histone variants, the variants of H2B remain largely understudied. Here, we show that H2B variants are dysregulated in breast cancer and that certain variants are associated with specific breast cancer subtypes. HIST1H2BO overexpression (in particular) is more common in Asian, African American/Black, and young female populations and is associated with a worse prognosis. In vitro studies show that H2B1O compacts nucleosome structure. Incorporating H2B1O into chromatin activates pro-inflammatory and oncogenic pathways, induces the epithelial-to-mesenchymal transition (EMT), and generates resistance to first-line chemotherapeutic agents. Thus, H2B1O acts much like an onco-histone, with H2B variant expression being a prognostic biomarker for breast cancer and a potential new target for drug therapies to enhance treatment efficacy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/627414v1_ufig1.gif" ALT="Figure 1"> View larger version (106K): org.highwire.dtl.DTLVardef@12c21dcorg.highwire.dtl.DTLVardef@631f3aorg.highwire.dtl.DTLVardef@1972244org.highwire.dtl.DTLVardef@14ab3b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Aberrant expression of histone H2B variants reshape chromatin and alter oncogenic gene expression programs

Chromatin architecture governs DNA accessibility and gene expression. Thus, any perturbations to chromatin can significantly alter gene expression programs and promote disease. Prior studies demonstrate that every amino acid in a histone is functionally significant, and that even a single amino acid substitution can drive specific cancers. We previously observed that naturally occurring H2B variants are dysregulated during the epithelial to mesenchymal transition (EMT) in bronchial epithelial cells. Naturally occurring H2B variants differ from canonical H2B by only a few amino acids, yet single amino acid changes in other histone variants (e.g., H3.3) can drive cancer. We therefore hypothesized that H2B variants might function like oncohistones, and investigated how they modify chromatin architecture, dynamics, and function. We find that H2B variants are frequently dysregulated in many cancers, and correlate with patient prognosis. Despite high sequence similarity, mutations in each H2B variant tend to occur at specific "hotspots" in cancer. Some H2B variants cause tighter DNA wrapping around nucleosomes, leading to more compact chromatin structures and reduced transcription factor accessibility to nucleosomal DNA. They also altered genome-wide accessibility to oncogenic regulatory elements and genes, with concomitant changes in oncogenic gene expression programs. Although we did not observe changes in cell proliferation or migration in vitro, our Gene Ontology (GO) analyses of ATAC-seq peaks and RNA-seq data indicated significant changes in oncogenic pathways. These findings suggest that H2B variants may influence early-stage, cancer-associated regulatory mechanisms, potentially setting the stage for oncogenesis later on. Thus, H2B variant expression could serve as an early cancer biomarker, and H2B variants might be novel therapeutic targets.

cancer biology↗

bioRxiv2024

Environmental DNA as a complementary tool for biodiversity monitoring: A multi-technique and multi-trophic approach to investigate cetacean distribution and feeding ecology

The use of environmental DNA (eDNA) to assess the presence of biological communities has emerged as a promising monitoring tool in the marine conservation landscape. Moreover, advances in Next-Generation Sequencing techniques, such as DNA metabarcoding, enable multi-species detection in mixed samples, allowing the study of complex ecosystems such as oceanic ones. We aimed at using these molecular-based techniques to characterise cetacean communities, as well as potential prey in the northern coast of Mainland Portugal. During seasonal campaigns, we collected seawater samples, along with visual records of cetacean occurrence. The eDNA extracted from 64 environmental samples was sequenced in an Illumina platform, with universal primers targeting marine vertebrates. Five cetacean species were identified by molecular detection: common dolphin (Delphinus delphis), bottlenose dolphin (Tursiops truncatus), Rissos dolphin (Grampus griseus), harbour porpoise (Phocoena phocoena) and fin whale (Balaenoptera physalus). Overall, except for the fin whale (not sighted during the campaigns), this cetacean community composition was similar to that obtained through visual monitoring, and the complementary results suggest their presence in the region all year round. In addition, the positive molecular detections of B. physalus are of special relevance since there are no visual records reported in the area. The detection of multiple known preys of the identified dolphins indicates they use these coastal areas for feeding purposes. While this methodological approach remains in a development stage, the present work highlights the benefits of using eDNA to study marine communities, with specific applications for research on cetacean distribution and feeding ecology, ultimately serving as the baseline of a methodological approach for biodiversity monitoring and marine conservation.

ecology↗

bioRxiv2024

Australian researchers' perceptions and experiences with stem cell registration.

The recently issued ISSCR standards in stem cell research recommend registration of human pluripotent stem cell lines (hPSCs). Registration is an important part of establishing stem cell provenance and connecting cell lines to data derived on those lines. In this study, we sought to understand common barriers to registration, by conducting interviews with forty-eight Australian stem cell stakeholders, including researchers, clinicians, and industry professionals. Australian stem cell researchers do not routinely register their lines, and of those Australian lines captured by an international registry, only a third have completed the registration process. Most registered Australian cell lines miss information about their ethical provenance or key pluripotency characteristics. Incomplete registration is poorly aligned with the goals of open science that registries are founded on, and users themselves expressed concerns about the quality of the partial information provided to the resource. Registration was considered a publication hurdle, and this impacted on user perceptions of usefulness of registration, and lowered the likelihood that they would engage with registries to find resources. Although the Australian community represents a small fraction of registry users, the results of this study may suggest ways for journals, registries, and the stem cell community to improve registration compliance. HighlightsResearchers who perceive registration as a publication hurdle are unlikely to complete the registration process. Incomplete registration promotes misunderstandings about the goals and quality of a registry. Full registration of pluripotent stem cell lines is an important step in verifying cell line provenance. Greater public awareness of registration, combined with requirements for full registration by journals will support the community adopt ISSCR recommendations to register lines.

scientific communication and education↗

bioRxiv2021

The proteome of remyelination is different from that of developmental myelination

Loss of myelin underlies the pathology of several neurological disorders of diverse etiology. CNS remyelination by adult oligodendrocyte progenitor cells (OPCs) can occur but it differs from developmental myelination carried out by neonatal OPCs. We asked whether the myelin proteome of remyelinated regions is changed. We compared the myelin proteome formed during development to the remyelination proteome attained after lysolecithin-induced demyelination in the mouse spinal cord. Mass-spectrometry analysis of iTRAQ labelled myelin protein lysates showed that the proteome of remyelination is different from that of developmental myelination, leading to profound changes in myelin protein content. Aside from known mediators of oligodendrocyte differentiation, we found proteome alterations included modulators of metabolism, cell signaling and actin cytoskeleton dynamics. Downregulating one candidate (FSCN1/Fascin1) was sufficient to partially hamper oligodendrocytes in-vitro. In summary, we identify the difference in the proteome of remyelinating oligodendrocytes as a novel potential contributor to the pathophysiology of demyelinating disorders, thus providing new potential therapeutic targets for future studies.

neuroscience↗