Biology subjects

Nogay, L.

Publications and source records attributed to Nogay, 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↗

bioRxiv2021

Sibling rivalry among the ZBTB transcription factor family: homo vs. heterodimers

The BTB domain is an oligomerization domain found in over 200 proteins encoded in the human genome. In the family of BTB domain and Zinc Finger-containing (ZBTB) transcription factors, 49 members share the same protein architecture. The N-terminal BTB domain is structurally conserved among the family members and serves as the dimerization site while the C-terminal zinc finger motifs mediate DNA binding. The available BTB domain structures from this family reveal a natural inclination for homodimerization. In this study we investigated the potential for heterodimer formation in the cellular environment. We selected five BTB homodimers and four heterodimer structures. We performed in vitro binding assays with fluorescent protein-BTB domain fusions to assess dimer formation. We tested the binding of several BTB pairs, and we were able to confirm the heterodimeric physical interaction between the BTB domains of PATZ1 and PATZ2, previously reported only in an interactome mapping experiment. We also found this pair to be co-expressed in several immune system cell types. Finally, we used the available structures of BTB domain dimers and newly constructed models in extended molecular dynamics simulations (500 ns) to understand the energetic determinants of homo and heterodimer formation. We conclude that heterodimer formation, although frequently described as less preferred than homodimers, is a possible mechanism to increase the combinatorial specificity of this transcription factor family.

molecular biology↗