Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.10.18.619049

Epigenetic modulation of RIPK3 by Transglutaminase 2-dependent serotonylation of H3K4me3 affects necroptosis

Vecchio, A.·Colasuonno, F.·Bellanca, V.·Pitolli, C.·Occhigrossi, L.·Ciccarone, F.·D'Eletto, M.·Di Sano, F.·Pagliarini, V.·Sette, C.·Piacentini, M.·Rossin, F.
View original source ↗Export metadata ↓

Abstract

The receptor interacting protein kinase 3 (RIPK 3) is the main player in the activation of necroptosis, a pro-inflammatory regulated cell death modality induced by many different stimuli. RIPK3 is epigenetically regulated by DNA methylation and can be expressed when its promoter is associated with H3K4me3 histone. In this study, we show that Transglutaminase 2 protein (TG2) is necessary to induce necroptosis pathway allowing the expression of Ripk3 gene. Indeed, cells lacking TG2 show a strong downregulation of Ripk3 gene and are resistant to necroptotic stimuli. TG2 is known to promote the serotonylation of H3K4me3 histone (H3K4me3Q5ser) regulating in this way the target gene expression. Interestingly, we find that TG2 interacts with both histones H3K4me3 and H3K4me3Q5ser and these post-translational modifications are associated with the Ripk3 promoter only in presence of TG2. In addition, the absence of the H3K4me3Q5ser, in cells lacking TG2, is correlated with Ripk3 gene methylation. Altogether, these results indicate that RIPK3 expression requires TG2 mediated serotonylation of H3K4me3 to prevent Ripk3 promoter methylation, thus favouring its expression and necroptosis induction. HIGHLIGHTS- Transglutaminase 2 protein (TG2) is necessary to induce necroptosis. - Cells lacking TG2 show a strong downregulation of Ripk3 gene. - TG2 allows Ripk3 gene expression by promoting the serotonylation on H3K4me3 histone. SYNOPSIS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/619049v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@12c95c6org.highwire.dtl.DTLVardef@1cfbcaorg.highwire.dtl.DTLVardef@d6be1forg.highwire.dtl.DTLVardef@5bfb31_HPS_FORMAT_FIGEXP M_FIG C_FIG - TG2 serotonylates histone H3K4me3, associated to Ripk3 promoter, favoring its expression. - TG2 dependent serotonylation of histone H3K4me3 prevents DNA methylation. - TG2 favours the expression of Ripk3 making cells susceptible to necroptosis. - In the absence of TG2, neither serotonylation nor methylation occur on histone H3, associated to Ripk3 promoter. - In the absence of TG2, Ripk3 promoter is methylated, thus blocking the activation of necroptosis.

Source connections

Explore related subjects

cell biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Vecchio, A., Colasuonno, F., Bellanca, V., Pitolli, C., Occhigrossi, L., Ciccarone, F., D'Eletto, M., Di Sano, F., Pagliarini, V., Sette, C., Piacentini, M., Rossin, F.. 2024-10-19. Epigenetic modulation of RIPK3 by Transglutaminase 2-dependent serotonylation of H3K4me3 affects necroptosis. https://doi.org/10.1101/2024.10.18.619049

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity

The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.

cell biology↗
bioRxiv2026

Nucleosome Core Allostery Governs Chromatin Recognition and Cell Fate

Nucleosomes regulate chromatin folding, accessibility, and factor recruitment. Current models primarily attribute these functions to histone tail modifications, while the core is largely viewed as a structural scaffold. Yet subtle changes within the nucleosome core can produce profound functional consequences, and the mechanisms underlying these effects remain unclear. Here, we describe nucleosome core allostery as a fundamental principle of chromatin regulation that amplifies the impact of minimal nucleosome variations. Leveraging natural differences between H2A.Z variants, we show that the nucleosome core encodes distinct conformational dynamics that propagate allosterically, thereby controlling nucleosome accessibility and recognition by chromatin factors. As a result, a single buried amino acid substitution alone is sufficient to reprogram nucleosome dynamics and bias cell identity. Our findings establish the nucleosome core as an allosteric regulatory module and provide a generalizable framework for how subtle variation within nucleosomes is amplified into diverse biological outcomes in development and disease.

cell biology↗
bioRxiv2026

YAP/TAZ-controlled ERK dynamics coordinate progenitor expansion and differentiation commitment

Progenitor cells must proliferate to expand the cell population, yet terminal differentiation requires this proliferative state to end. How signaling controls the duration of this proliferative window remains poorly understood. Using adipogenesis and live single-cell imaging of differentiation, cell-cycle, and ERK-activity reporters, we show that YAP and TAZ coordinate progenitor expansion with differentiation commitment by regulating ERK dynamics. YAP/TAZ maintain cells in a fluctuating high-ERK state that promotes proliferation while actively keeping the differentiation driver PPARG below the threshold for irreversible commitment. Crucially, this differentiation block is not explained by proliferation alone: inhibiting CDK4/6 or AKT suppressed proliferation without restoring differentiation, whereas MEK-ERK inhibition restored differentiation even when YAP/TAZ activity remained high. As YAP/TAZ activity decreases, dampened ERK fluctuations trigger PPARG activation. These findings support a self-limiting model in which YAP/TAZ-driven progenitor expansion progressively increases cell density and contact-dependent Hippo signaling, reducing YAP/TAZ activity and terminating the proliferative phase. Consequently, transient YAP/TAZ activation expands the progenitor pool while preserving subsequent differentiation, whereas sustained activation suppresses commitment. Together, these findings identify YAP/TAZ-controlled ERK dynamics as the nexus coordinating progenitor expansion with terminal differentiation and suggest that slower density-dependent Hippo feedback may set the duration of this proliferative window to regulate differentiated cell-number output.

cell biology↗