Biology subjects

Palma, F. R.

Publications and source records attributed to Palma, F. R..

4 recordsLinked to original sources

bioRxiv2025

O-SNAP: A comprehensive pipeline for spatial profiling of chromatin architecture

We present O-SNAP (Objective Single-Molecule Nuclear Architecture Profiler), a comprehensive pipeline for the automated extraction, comparison, and classification of nuclear features from single-molecule localization microscopy (SMLM) data. O-SNAP quantifies 144 interpretable, biologically grounded spatial features describing chromatin organization or histone mark distributions at nanoscale resolution. The pipeline includes modules for pairwise comparison of features using volcano plots, feature set enrichment analysis, robust feature selection and classification of cell states, and pseudotime trajectory inference. We validate O-SNAP across diverse biological contexts, including fibroblast-to-stem cell reprogramming, tendon disease, histone variant sensitivity to oxidative stress, and chondrocyte de-differentiation, demonstrating its ability to detect subtle changes in nanoscale chromatin organization across diverse biological transitions.

biophysics↗

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

Metabolic shift to serine pathway induced by lipids confers oncogenic properties in non-transformed breast cells

A lipid metabolism gene signature is associated with the risk of estrogen negative breast cancer (ER-BC). In vitro, lipid exposure alters histone methylation affecting gene expression and increasing flux through various metabolic reactions; but little is known about the mechanism(s) linking lipids and epigenetic reprogramming with the genesis of ER-BC. Here we show that the metabolism of the medium-chain fatty acid Octanoic Acid (OA) in preference to glucose and glutamine results in a metabolic shift toward the serine pathway increasing the production of SAM, glutathione, and 2-HG, with implications for oncogenesis: SAM production results in epigenetic fostered plasticity leading to reprogramming/selecting cells that express Neural, EMT and BC related genes. 2-HG exposure results in appearance of DNA breaks, potentially consequent to the inhibition of essential demethylases for HR repair. ROS increases shortly after OA exposure and is mitigated by antioxidant defenses, which favors/enables the survival of specific cell subtypes.

cancer biology↗

bioRxiv2022

H3.1Cys96 oxidation by mitochondrial ROS promotes chromatin remodeling, breast cancer progression to metastasis and multi-drug resistance

Transcription stability enforces cellular identity and is tightly controlled by restrictions imposed on both transcription factor function and target gene accessibility. Progression of cancer to metastasis and multi-drug resistance requires fluid transcriptional programs that can explore different genomic landscapes to enable clonal expansion of aggressive and treatment resistant phenotypes. Here, we show that increased levels of H2O2 produced in mitochondria leads to H3.1 oxidation at Cys96, a distinctive redox sensitive amino acid residue restricted to this histone variant, in the nucleus. The oxidation of Cys96 promotes the eviction of H3.1 from chromatin and its exchange with H3.3, thereby opening silenced portions of the chromatin. Mutation of Cys96 by an oxidation-resistant serine residue or quenching nuclear H2O2 reversed chemotherapy resistance and drove established metastatic disease into remission. Together, these results show that increased mitochondrial H2O2 production, characteristic of metabolic dysfunction, promotes transcriptional plasticity by removing structural chromatin restrictions imposed by the redox sensitive histone variant H3.1. We suggest that this new regulatory nexus between cancer metabolism and chromatin remodeling controls chromatin states that enable cancer progression and drug resistance acquisition.

cancer biology↗