Biology subjects

Heckmann, L.

Publications and source records attributed to Heckmann, L..

3 recordsLinked to original sources

bioRxiv2025

Cell cycle dynamics regulate H3K27 and H3K9 histone modifications

Cell cycle progression presents a fundamental challenge to genome integrity, particularly due to the need to reestablish post-translational histone modifications (PTMs) following DNA replication. Although proliferative and differentiating tissues exhibit markedly different cell cycle dynamics, how these differences shape the histone modification landscape in vivo remains largely unexplored. Here, we show that levels of H3K27ac, H3K27me3, and H3K9me3 are tightly linked to cell cycle dynamics in the Drosophila wing imaginal disc. We demonstrate that both physiological and pathological elongation of the cell cycle led to an accumulation of H3K9me3 and H3K27me3, whereas cell cycle acceleration reduces their levels. In contrast, H3K27ac exhibits the opposite pattern: levels decrease in arrested cells and increase with faster cycling. Genome-wide CUT&Tag analysis reveals that these changes predominantly affect genomic loci already modified in normally proliferating tissue. Importantly, the regulation of methylation levels at H3K9 and H3K27 is not solely mediated by the cell cycle machinery but reflects a metabolically guided process in which the rate of methylation is coupled to the rate of cell proliferation through metabolic activity, including signaling via the Insulin/PI3K/Akt pathway. Our study thus reveals key principles for understanding histone methylation in proliferating, senescent, and differentiating cells. In contrast, H3K27 acetylation is regulated through a distinct, cell cycle-coupled mechanism. We find that CBP/Nejire-mediated acetylation of H3K27 peaks during S-phase and is reversed by HDAC1, as cells exit replication. Disruption of this acetylation cycle leads to replication stress and a G2 cell cycle arrest via a DNA damage checkpoint. Notably, this genome-protective function of CBP/Nejire depends specifically on acetylation of the H3K27 residue itself, revealing a novel role for H3K27ac beyond its well-established function in transcriptional activation. Together, our findings establish a robust link between cell cycle progression and histone modification dynamics, highlighting the necessity of maintaining balanced PTM levels under varying proliferative states. These insights have broad implications for our understanding of development, aging, and tumor growth.

cell biology↗

bioRxiv2024

PDK-1/S6K and mTORC1 bypass systemic growth restrictions to promote regeneration

Inflammation triggers systemic signals that induce growth restrictions in distant organs, a process well characterized in tumor cachexia. While mechanisms allowing tumors to circumvent these systemic growth restrictions have been established, the physiological processes that overcome inflammation-induced growth restrictions during regeneration remain largely unexplored. In our study, we use a model of tissue inflammation and regeneration in developing Drosophila imaginal discs to dissect key metabolic and signaling adaptations that, in physiological settings, both induce and overcome systemic growth restrictions. We find that expression of eiger, the Drosophila TNF- homolog, induces systemic insulin restriction, as evidenced by reduced expression of dILP2 and dILP5, as well as elevated nuclear dFOXO, and reduced protein translation and proliferation in peripheral tissues. Proliferating cells overcome systemic insulin restriction by upregulating Pdk1, which is both necessary and sufficient to promote phosphorylation of ribosomal protein S6 and protein translation via an Insulin/Akt-independent mechanism. We further demonstrate that JAK/STAT signaling acts upstream to increase Pdk1 levels, delineating a novel JAK/STAT-Pdk1-S6K axis essential for regenerative proliferation. The upregulation of amino acid transporters in the proliferative domain further suggests that regenerating cells preferentially import amino acids, fueling mTORC1 activation. Similar metabolic signatures are observed in a Drosophila RasV12, scrib tumor model, suggesting that tumors may co-opt these metabolic pathways to sustain growth in an insulin-restricted environment. Our findings reveal a specialized metabolic program that integrates systemic nutrient mobilization with local metabolic reprogramming, with important implications for understanding of physiological tissue repair but also pathologies such as chronic wounds and cancer.

developmental biology↗

bioRxiv2020

Substrate Resistance to Traction Forces Controls Fibroblast Polarization

The mechanics of fibronectin-rich extracellular matrix regulate cell physiology in a number of diseases, prompting efforts to elucidate cell mechanosensing mechanisms at the molecular and cellular scale. Here, the use of fibronectin-functionalized silicone elastomers that exhibit considerable frequency-dependence in viscoelastic properties unveiled the presence of two cellular processes that respond discreetly to substrate mechanical properties. Soft elastomers supported efficient focal adhesion maturation and fibroblast spreading due to an apparent stiff surface layer. However, soft elastomers did not enable cytoskeletal and fibroblast polarization; elastomers with high cross-linking and low deformability were required for polarization. The underlying reason for this behavior was the inability of soft elastomeric substrates to resist traction forces, rather than a lack of sufficient traction force generation; accordingly, mild inhibition of actomyosin contractility rescued fibroblast polarization even on the softer elastomers. Our findings help reconcile previously proposed local and global models of cell mechanosensing by demonstrating the differential dependence of substrate mechanics on distinct cellular processes. Statement of SignificanceThe mechanisms cells employ to sense and respond to the mechanical properties of their surroundings remain incompletely understood. In this study we used a commercial silicone elastomer formulation to prepare compliant, fibronectin-coated substrates and investigate the adhesion and polarization of human fibroblasts. Our results suggest the existence of at least two discrete mechanosensing processes regulated at different time and length (force) scales. Focal adhesion assembly and cell spreading were promoted by a stiff surface layer independent from bulk viscoelasticity, whereas effective cell polarization required elevated elastomer stiffness, sufficient to resist applied cell traction. The results presented here have implications on the use of elastomeric substrates as biomaterials for mechanosensing studies or clinical applications.

biophysics↗