Biology subjects

Dupre, P.

Publications and source records attributed to Dupre, P..

5 recordsLinked to original sources

bioRxiv2026

THE MULTIFUNCTIONAL PROTEIN E4F1 REGULATES MELANOCYTIC FUNCTIONS IN MICE THROUGH PROTEIN TRANSLATION AND MITF EXPRESSION

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of skin homeostasis, playing a critical role in epidermal stem cell maintenance and keratinocyte differentiation. However, the functions of E4F1 in other skin cell type remain poorly investigated. Here, we describe its role in melanogenesis, the physiological process for synthesis of melanin pigments. Using genetically engineered mouse models that enabled conditional inactivation of E4f1 specifically in melanocytes, we demonstrated that E4f1 loss induces severe pigmentation defects without affecting melanocyte survival nor differentiation. At the molecular level, E4f1 depletion reduces the expression of its direct transcriptional target genes involved in protein translation, including Elp3 and Eef1g, leading to translation alterations and consequently the induction of the Integrated Stress Response (ISR). This response resulted in microphthalmia-associated transcription factor (MITF) downregulation, inducing a decrease in the expression of enzymes involved in melanin synthesis. Consistent with these findings, Elp3 or Eef1g depletion recapitulated the decrease in MITF levels in vitro, and pharmacological inhibition of ISR partially rescued melanin content in vivo, confirming a key role of the E4F1-protein translation-ISR cascade in melanogenesis. Together, our data identify E4F1-associated translation functions as a key regulator of the melanocytic lineage.

physiology↗

bioRxiv2026

Androgen Receptor mediates beige adipocyte homeostasis and plasticity

Male adipose tissue undergoes profound post-pubertal remodeling characterized by the progressive transition of beige adipocytes toward a white adipocyte phenotype. Although androgen signaling has been implicated in adipose tissue biology, its role in beige adipocyte remodeling and metabolic plasticity remains poorly understood. Here we show that androgen receptor (AR) signaling is dynamically activated in inguinal white adipose tissue during the post-pubertal beige-to-white transition in male mice. Inducible deletion of AR in beige adipocytes impaired this remodeling process, resulting in the persistence of multilocular beige-like adipocytes despite reduced thermogenic competence and marked mitochondrial abnormalities. Transcriptomic and cistromic analyses identified AR as a direct regulator of adipocyte metabolic and differentiation programs, whereas immune-related transcriptional signatures in AR-deficient adipose tissue primarily reflected macrophage infiltration and inflammatory remodeling. Loss of AR promoted mitochondrial dysfunction, mitophagy, and altered glucose handling, while cell-autonomous AR silencing in beige adipocytes recapitulated key defects in mitochondrial organization and adipocyte identity. Longitudinal and metabolic challenge studies further demonstrated that AR signaling is required for age-associated adipose remodeling and adaptive beige adipocyte plasticity during high-fat diet feeding and cold exposure. Together, these findings identify AR as a central regulator of beige adipocyte remodeling, mitochondrial homeostasis, and adaptive metabolic function in male adipose tissue.

physiology↗

bioRxiv2024

Acute dietary methionine restriction highlights sensitivity of neocortex development to metabolic variations

Methionine -an essential amino acid that has to be provided by nutrition- and its metabolite S-Adenosyl methionine (SAM) are indispensable for cell proliferation, stem cell maintenance and epigenetic regulation 1-5, three processes that are central to embryonic development 6. Previous studies using chronic dietary restriction of methyl donors prior to and during gestation indicated that methionine restriction (MR) is detrimental to the development or growth of the neocortex 7,8, however, the consequences of acute MR have not been extensively studied. Here, we designed a dietary MR regime coinciding with the neurogenic phases of neocortex development in the mouse. Our results indicate that dietary MR for 5 days leads to a severe reduction in neocortex growth and neuronal production. In comparison, growth of the liver and heart was unaffected, highlighting an organ-specific response to MR which was also observed at the cellular and molecular levels. Progenitor cohort labeling revealed a time-dependent sensitivity to MR and cell cycle analyses indicated that after 5 days of MR, progenitors are stalled in the S/G2 phases. Unexpectedly, neocortex growth reduction induced after 5 days of MR is completely rescued at birth when switching the dam back to control diet for the remaining of gestation, uncovering a mechanism of catch-up growth. Using multiplexed imaging we probed metabolic and epigenetic markers following MR and during catch-up growth and show that pyruvate metabolism is rewired in progenitors. Altogether, our data uncover a transient state of quiescence in G2/S which is metabolically distinct from G0 quiescence and associated with efficient catch-up growth. More globally, our study highlights both the extreme sensitivity of the developing neocortex to acute dietary changes and its remarkable plasticity.

developmental biology↗

bioRxiv2024

Deciphering Oxygen Distribution and Hypoxia Profiles in the Tumor Microenvironment: A Data-Driven Mechanistic Modeling Approach

The distribution of hypoxia within tissues plays a critical role in tumor diagnosis and prognosis. Recognizing the significance of tumor oxygenation and hypoxia gradients, we introduce mathematical frameworks grounded in mechanistic modeling approaches for their quantitative assessment within a tumor microenvironment. Our approach provides a non-invasive method to measure and predict hypoxia using known blood vasculature. Formulating a reaction-diffusion model for oxygen distribution, we apply it to derive the corresponding hypoxia profile. The modeling and simulations successfully replicate the observed inter- and intra-tumor heterogeneity in experimentally obtained hypoxia profiles across various tumor tissues (breast, ovarian, and pancreatic) in our dataset. Employing a data-driven approach, we propose a method to deduce partial differential equation (PDE) models with spatially dependent parameters, enabling us to comprehend the variability of hypoxia profiles within a tissue. The versatility of our framework lies not only in capturing diverse and dynamic behaviors of tumor oxygenation but also in categorizing states of vascularization. These categories are distinguished based on the dynamics of oxygen molecules, as identified by the model parameters.

cancer biology↗

bioRxiv2022

E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE PROTEIN TRANSLATION FIDELITY DURING NEURONAL DEVELOPMENT

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pathogenesis. We identified the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensured proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlighted a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

developmental biology↗