Biology subjects

Esteve, P. O.

Publications and source records attributed to Esteve, P. O..

4 recordsLinked to original sources

bioRxiv2026

Altered chromatin accessibility and nucleosome positioning landscape upon HDAC and LSD1 inhibition in cancer cell

Epigenetic enzymes, writers, readers and erasers regulate chromatin landscapes and participate in tumor heterogeneity. While therapeutic targeting of these enzymes has shown clinical promise, the comparative efficacy of mono-versus dual-inhibitor strategies remain unclear. Here, we introduce a multi-modal platform that uses NicE-viewSeq and integrates automated deep learning based spatially resolved chromatin accessibility profiling with high-throughput sequencing following epigenetic inhibitor application. Accessible chromatin landscapes were altered along with nucleosome positioning following inhibition of either LSD1 or HDACs alone, or both together. Coordinated modulation of histone marks and the CoREST complex on chromatin was observed across inhibitory conditions. Transcription factor binding analysis identified three predominant families, ETS, RUNT, and bZIP with enhanced chromatin association upon treatments. Mechanistically, a CoREST-RUNX regulatory axis was uncovered wherein JunB, a member of bZIP family displaces CoREST-RUNX at differentially accessible regions, triggering apoptotic pathways. Therefore, JunB-mediated mechanism reveals a convergent therapeutic vulnerability, offering new avenues for optimizing different combinatorial epigenetic therapy in cancer.

genetics↗

bioRxiv2025

NPM1 mislocalization mediated by RNA Pol I inhibition alters chromatin landscape

RNA polymerase I inhibition affects rRNA synthesis from rDNA clusters residing in nucleolar organizer regions (NORs). Here we have demonstrated RNA Pol I inhibition disrupts nucleolar architecture, NPM1 localization, and alters the chromatin landscape using coordinated eraser and writer enzymes. siRNA mediated depletion or dissociation of NPM1 allows HDAC1 loading on the chromatin. HDAC1 mediated deacetylation of H3K9ac creates H3K9 that undegoes SUV39H1-mediated methylation. The stripping of active histone marks leads to enrichment of repressive H3K9me3 in the genome. These altered chromatin landscape corroborates with loss of genome-wide chromatin accessibility and DNA hypermethylation mediated by DNMT1. Chromatin architectural analysis revealed disrupted nucleolar associated domains (NADs) transforming to lamin associated domains (LADs) with specific histone signatures and repressive states. The 3D nuclear architecture was remodeled by A/B compartments reorganization and loss of Hi-C loops at the H3K9ac depleted sites.

molecular biology↗

bioRxiv2024

Distinct structural and functional heterochromatin partitioning of lamin B1 and B2 revealed using genome-wide Nicking Enzyme Epitope targeted DNA sequencing.

A genome-wide chromatin profiling technology, named as Nicking Enzyme Epitope targeted DNA sequencing (NEED-seq) in which antibody-targeted controlled nicking by Nt.CviPII-pGL is used to study specific protein-DNA complexes. NEED-seq is performed in situ in formaldehyde fixed cells, allowing for both visual and genomic resolution of epitope bound chromatin. When applied to nuclei, NEED-seq yielded genome-wide chromatin associated proteins and histone post-translational modifications (PTMs). NEED-seq of lamin B1/B2 demonstrated their association with heterochromatin. Lamin B1 and B2 associated domains (LAD) segregated to three different states, and states with stronger LAD correlated with heterochromatic marks. Hi-C analysis displayed A and B compartment with equal lamin B1/B2 distribution, although methylated DNA remained high in B compartment. LAD clustering with Hi-C resulted in subcompartments, with lamin B1-B2 partitioning to facultative and constitutive heterochromatin respectively and were associated with neuronal development. Thus, lamin B1 and B2 have structural and functional partitioning in mammalian nucleus. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/603107v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@44c36forg.highwire.dtl.DTLVardef@7ab1adorg.highwire.dtl.DTLVardef@126e99eorg.highwire.dtl.DTLVardef@1b38bd7_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Graphical abstract: Model depicting association of lamin B1 and B2 in A (facultative heterochromatin) and B (constitutive heterochromatin) compartmentalization. C_FIG

genomics↗

bioRxiv2019

Transcription factor LSF facilitiates lysine methylation of α-tubulin by microtubule-associated SET8

Microtubules are critical for mitosis, cell motility, and protein and organelle transport, and are a validated target for anticancer drugs. However, tubulin regulation and recruitment in these cellular processes is less understood. Post-translational modifications of tubulin are proposed to regulate microtubule functions and dynamics. Although many such modifications have been investigated, tubulin methylations and enzymes responsible for methylation have only recently begun to be described. Here we report that N-lysine methyl transferase KMT5A (SET8/PR-Set7), which methylates histone H4K20, also methylates -tubulin. Furthermore, the transcription factor LSF binds both tubulin and SET8, and enhances -tubulin methylation in vitro, countered by FQI1, a specific small molecule inhibitor of LSF. Thus, the three proteins SET8, LSF, and tubulin, all essential for mitotic progression, interact with each other. Overall, these results point to dual functions for both SET8 and LSF not only in chromatin regulation, but also for cytoskeletal modification.

biochemistry↗