Biology subjects

Martinelli, V.

Publications and source records attributed to Martinelli, V..

14 recordsLinked to original sources

bioRxiv2026

Identification of a key residue in the cellular transcription factor BCL11b important for its global acetylation and its nuclear localization

AO_SCPLOWBSTRACTC_SCPLOWThe cellular transcription factor BCL11b (B-cell CLL/lymphoma 11b) interacts with numerous cellular and viral factors to modulate gene expression positively or negatively. Post-translational modifications of BCL11b, such as SUMOylation and phosphorylation, have been documented to switch its transcriptional activity from a repressor to an activator state. In the present study, we investigated the acetylation of BCL11b and we identified the histone acetyltransferase p300 as able to acetylate BCL11b. Subsequently, we observed that the mutation of the lysine K686 residue of BCL11b (BCL11b K686R) influenced its global acetylation. Furthermore, the BCL11b K686R mutation also modulated the transcriptional regulation of BCL11b, including its activity in regulating the p21 and IL-2 promoters. This effect on transcriptional regulation was due to the importance of the lysine K686 residue for BCL11b nuclear localization. Our results underscore the critical role of the lysine K686 residue in BCL11b for its interaction with p300 and its nuclear localization, suggesting a possible function of p300 in the nuclear transport of BCL11b. Collectively, our findings contribute to a better understanding of BCL11b-mediated gene expression and of the interactions of BCL11b with cellular partners.

molecular biology↗

bioRxiv2026

Microtubule detyrosination enhances matrix remodeling and force transmission during endothelial sprouting

Angiogenic sprouting relies on the coordinated regulation of endothelial migration, force generation, and extracellular matrix (ECM) remodeling. While microtubules are known to regulate cell polarity and migration, how tubulin post-translational modifications reshape microtubule behavior and impact matrix-dependent migration programs remain unclear. Here, using sprouting angiogenesis as an integrative physiological context, we combine live-cell imaging, three-dimensional (3D) sprouting and microfluidic invasion assays, and 3D traction force microscopy to dissect the role of tubulin detyrosination and acetylation. We show that microtubule detyrosination, in contrast to acetylation, promotes directional persistence, sprout elongation and collective endothelial invasion. Detyrosinated microtubules remain dynamic and display more persistent growth, supporting sustained directional migration. Strikingly, microtubule detyrosination also enhances ECM remodeling, leading to increased matrix degradation and augmented traction force transmission. Functional inhibition experiments reveal that matrix degradation, rather than actomyosin contractility, is required for both elevated forces and enhanced sprouting. Together, these findings identify microtubule detyrosination as a key regulator linking cytoskeletal dynamics, cell migration and matrix remodeling during angiogenesis.

cell biology↗

bioRxiv2025

Integrated metabolomic and metagenomic profiling reveals distinct signatures in treatment naive multiple sclerosis patients.

Imbalances in gut microbiota composition and microbiota-associated metabolites have been linked with several neurological diseases, including multiple sclerosis (MS). However, a comprehensive multi-biofluid approach remains lacking. Most studies on MS include patients already receiving treatment and often neglect to account for sex-related differences, which could serve as potential confounding factors. Moreover, they mostly investigate only stools or plasma metabolomics. In this study, we recruited 18 treatment-naive neuroinflammatory patients at diagnosis and compared them with 20 healthy controls, matched for sex and age. We conducted multi-biofluids metabolomic analysis of urine, stool, serum, and cerebrospinal fluid, complemented by taxonomical and functional profiling of the gut microbiome using shotgun metagenomic sequencing. Our results show that MS patients exhibit distinct microbiome composition and urinary metabolomic profiles compared to healthy controls. Furthermore, neuroinflammation is associated with dysregulation of microbially-produced short-chain fatty acids, their intestinal absorption and systemic bioavailability, as illustrated by the altered plasma levels.

neuroscience↗

bioRxiv2025

Root Contours Guided Design of a Multicellular PID Controller

Ensuring a stable and robust phenotype expression is a key challenge for the correct operation of synthetically engineered cells, and feedback has been highlighted as a key mechanism to achieve this goal. Biomolecular PID controllers have been extensively leveraged at a single cell level to regulate gene expression. However, single-cell architectures suffer from limited modularity and might pose a significant challenge for their in vivo implementation due to high metabolic load and possible incompatible reactions. To overcome these limitations, it has been proposed to distribute the control actions over different cell populations realizing a multicellular feedback control architecture. In this paper we provide design guidelines derived by means of the root contours method to tune the control gains of a multicellular PID controller. We then validate performance, robustness and modularity of the multicellular PID controller through in silico simulations in BSim.

synthetic biology↗

bioRxiv2025

Regulating population density through antithetic feedback control of cell growth

We present a genetic feedback control strategy enabling engineered microorganisms to self-regulate their population density. Our approach leverages a quorum sensing mechanism for the production of a growth inhibitor protein, whose activation is regulated by an embedded antithetic controller. Through mathematical modeling and steady-state analysis, we provide design guidelines to tune the control parameters. Finally, we validate the control architecture performance and robustness via realistic agent-based simulations in BSim. The proposed control architecture guarantees robust regulation of the cell density while relying on fewer constraints on the biological parameters with respect to other solutions presented in the literature.

synthetic biology↗

bioRxiv2024

In silico analysis of metabolic burden effects on a multicellular integral controller

Metabolic burden is a critical limiting factor in the design of synthetic circuits, affecting both their reliability and performance. To mitigate its effects, distributing control functions across different cell populations within a multicellular control architecture offers a promising solution, while simultaneously enhancing modularity and re-usability of the circuits. We first present a model that explicitly accounts for limited ribosome availability within cells. Using this framework, we then derive a mathematical model of a multicellular antithetic integral controller that incorporates these shared resources. Through numerical bifurcation analysis and in silico agent-based experiments in BSim, we compare the multicellular controller against its traditional single-cell (embedded) implementation, evaluating both resource utilization and stability.

synthetic biology↗

bioRxiv2024

Multicellular Proportional-Integral-Derivative Control for Robust Regulation of Biological Processes

This paper presents the first implementation of a Proportional-Integral-Derivative (PID) biomolecular controller within a consortium of different cell populations, aimed at robust regulation of biological processes. By leveraging the modularity and cooperative dynamics of multiple engineered cell populations, we develop a comprehensive in silico analysis of the performance and robustness of P, PD, PI, and PID control architectures. Our theoretical findings, validated through in silico experiments using the BSim agent-based simulation platform, demonstrate the robustness and effectiveness of our multicellular PID control strategy. This innovative approach addresses critical limitations in current control methods, offering significant potential for applications in metabolic engineering, therapeutic contexts, and industrial biotechnology. Future work will focus on experimental validation in vivo and further refinement of the control models.

synthetic biology↗

bioRxiv2023

Alteration of actin cytoskeletal organisation in fetal akinesia deformation sequence

Fetal akinesia deformation sequence (FADS) represents the severest form of congenital myasthenic syndrome (CMS), a diverse group of inherited disorders characterised by impaired neuromuscular transmission. Most CMS originate from defects in the muscle nicotinic acetylcholine receptor, but the underlying molecular pathogenesis is only poorly understood. Here we show that RNAi-mediated silencing of FADS-related proteins rapsyn and NUP88 in foetal fibroblasts alters organisation of the actin cytoskeleton. We show that fibroblasts from two independent FADS individuals have enhanced and shorter actin stress fibre bundles, alongside with an increased number and size of focal adhesions, with an otherwise normal overall connectivity and integrity of the actin-myosin cytoskeleton network. By proximity ligation assays and bimolecular fluorescence complementation, we show that rapsyn and NUP88 localise nearby adhesion plaques and that they interact with the focal adhesion protein paxillin. Based on these findings we propose that a respective deficiency in rapsyn and NUP88 in FADS alters the regulation of actin dynamics at focal adhesions, and thereby may also plausibly dictate myofibril organisation and contraction in skeletal muscle of FADS individuals.

cell biology↗

bioRxiv2023

Multicellular PD Control in Microbial Consortia

We propose a multicellular implementation of a biomolecular PD feedback controller to regulate gene expression in a microbial consortium. The implementation involves distributing the proportional and derivative control actions between two different cellular populations that can communicate with each other and regulate the output of a third target cellular population. We derive analytical conditions on biological parameters and control gains to adjust the systems static and dynamical properties. We then validate the strategys performance and robustness through extensive in silico experiments.

synthetic biology↗

bioRxiv2022

Multicellular PI control for gene regulation in microbial consortia

We describe two multicellular implementations of the classical P and PI feedback controllers for the regulation of gene expression in a target cell population. Specifically, we propose to distribute the proportional and integral actions over two different cellular populations in a microbial consortium comprising a third target population whose output needs to be regulated. By engineering communication among the different cellular populations via appropriate orthogonal quorum sensing molecules, we are able to close the feedback loop across the consortium. We derive analytical conditions on the biological parameters guaranteeing the regulation of the output of the target population and we validate the robustness and modularity of proposed control schemes via in silico experiments in BSim, a realistic agent-based simulator of bacterial populations.

synthetic biology↗

bioRxiv2020

Mitotic checkpoint protein Mad1 is required for early Nup153 recruitment to chromatin and nuclear envelope integrity

The nucleoporin Nup153 is a multifunctional protein and the mitotic checkpoint protein Mad1one of its many binding partners. The functional relevance of their interaction has remained elusive. Here, we have further dissected Nup153s and Mad1s interface and functional interplay. By in situ proximity ligation assays, we found that the presence of a nuclear envelope (NE) is prerequisite for the Nup153-Mad1 interaction. Time-lapse microscopy revealed that depletion of Mad1 delayed recruitment of Nup153 to anaphase chromatin, which was often accompanied by a prolongation of anaphase. Furthermore, as seen by electron microscopic and three-dimensional structured illumination investigations, Nup153 and Mad1 depletion led to alterations in NE architecture, characterised by a change of the membrane curvature at nuclear pore complexes (NPCs) and an expansion of the spacing between the inner and outer nuclear membranes. Nup153 depletion, but not of Mad1, caused defects in interphase NPC assembly with partial displacement of cytoplasmic nucleoporins and a reduction in NPC density. Together our results suggest that Nup153 has separable roles in NE and NPC formation: in post-mitotic NE reformation in concert with Mad1 and in interphase NPC assembly, independent of Mad1. SummaryThe mitotic checkpoint protein is required for Nup153 recruitment to anaphase chromatin and in turn post-mitotic, but not interphase nuclear pore complex assembly.

cell biology↗

bioRxiv2020

Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage

HIV-1 latency generates reservoirs that prevent viral eradication by the current therapies. To find strategies toward an HIV cure, detailed understandings of the molecular mechanisms underlying establishment and persistence of the reservoirs are needed. The cellular transcription factor KAP1 is known as a potent repressor of gene transcription. Here we report that KAP1 represses HIV-1 gene expression in myeloid cells including microglial cells, the major reservoir of the central nervous system. Mechanistically, KAP1 interacts and colocalizes with the viral transactivator Tat to promote its degradation via the proteasome pathway and repress HIV-1 gene expression. In myeloid models of latent HIV-1 infection, the depletion of KAP1 increased viral gene elongation and reactivated HIV-1 expression. Bound to the latent HIV-1 promoter, KAP1 associates and cooperates with CTIP2, a key epigenetic silencer of HIV-1 expression in microglial cells. In addition, Tat and CTIP2 compete for KAP1 binding suggesting a dynamic modulation of the KAP1 cellular partners upon HIV-1 infection. Altogether, our results suggest that KAP1 contributes to the establishment and the persistence of HIV-1 latency in myeloid cells.

molecular biology↗

bioRxiv2020

Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines with NUP214 rearrangements

Chromosomal translocations fusing the locus of nucleoporin NUP214 each with the proto-oncogenes SET and DEK are recurrent in, largely intractable, acute leukemias. The molecular basis underlying the pathogenesis of SET-NUP214 and DEK-NUP214 are still poorly understood, but both chimeras inhibit protein nuclear export mediated by the {beta}-karyopherin CRM1. In this report, we show that SET-NUP214 and DEK-NUP214 both disturb the localization of proteins essential for nucleocytoplasmic transport, in particular for CRM1-mediated protein export. Endogenous and exogenous SET-NUP214 and DEK-NUP214 form nuclear bodies. These nuclear bodies disperse upon targeted inhibition of CRM1 and the two fusion proteins re-localize throughout the nucleoplasm. Moreover, SET-NUP214 and DEK-NUP214 nuclear bodies reestablish shortly after removal of CRM1 inhibitors. Likewise, cell viability, metabolism, and proliferation of leukemia cell lines harboring SET-NUP214 and DEK-NUP214 are compromised by CRM1 inhibition, which is even sustained after clearance from CRM1 antagonists. Our results indicate CRM1 as a possible therapeutic target in NUP214-related leukemia. This is especially important, since no specific or targeted treatment options for NUP214 driven leukemia are available yet.

cancer biology↗

bioRxiv2018

Mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence

Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, are of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are only rescued by expressing wild-type nup88 and not the disease-linked mutant forms of nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.

cell biology↗