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Article ; Online: Cleavage and polyadenylation machinery as a novel targetable vulnerability for human cancer.

Pagani, Giulia / Gandellini, Paolo

2024

Abstract: The role of alternative polyadenylation of mRNA in sustaining aggressive features of tumors is quite well established, as it is responsible for the 3'UTR shortening of oncogenes and subsequent relief from miRNA-mediated repression observed in cancer ... ...

Abstract	The role of alternative polyadenylation of mRNA in sustaining aggressive features of tumors is quite well established, as it is responsible for the 3'UTR shortening of oncogenes and subsequent relief from miRNA-mediated repression observed in cancer cells. However, the information regarding the vulnerability of cancer cells to the inhibition of cleavage and polyadenylation (CPA) machinery is very scattered. Only few recent reports show the antitumor activity of pharmacological inhibitors of CPSF3, one among CPA factors. More in general, the fact that deregulated CPA can be seen as a new hallmark of cancer and as a potential reservoir of novel therapeutic targets has never been formalized. Here, to extend our view on the potential of CPA inhibition (CPAi) approaches as anticancer therapies, we systematically tested the fitness of about one thousand cell lines of different cancer types upon depletion of all known CPA factors by interrogating genome-scale CRISPR and RNAi dependency maps of the DepMap project. Our analysis confirmed core and accessory CPA factors as novel vulnerabilities for human cancer, thus highlighting the potential of CPAi as anticancer therapy. Among all, CPSF1 appeared as a promising actionable candidate for drug development, as it showed low dependency scores pancancer and particularly in highly proliferating cells. In a personalized medicine perspective, the observed differential vulnerability of cancer cell lines to selected CPA factors may be used to build up signatures to predict response of individual human tumors to CPAi approaches.
Language	English
Publishing date	2024-04-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1212513-1
ISSN	1476-5500 ; 0929-1903
ISSN (online)	1476-5500
ISSN	0929-1903
DOI	10.1038/s41417-024-00770-y
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Article ; Online: Navigating the Multiverse of Antisense RNAs: The Transcription- and RNA-Dependent Dimension.

Pagani, Giulia / Pandini, Cecilia / Gandellini, Paolo

Non-coding RNA

2022 Volume 8, Issue 6

Abstract: Evidence accumulated over the past decades shows that the number of identified antisense transcripts is continuously increasing, promoting them from transcriptional noise to real genes with specific functions. Indeed, recent studies have begun to unravel ...

Abstract	Evidence accumulated over the past decades shows that the number of identified antisense transcripts is continuously increasing, promoting them from transcriptional noise to real genes with specific functions. Indeed, recent studies have begun to unravel the complexity of the antisense RNA (asRNA) world, starting from the multidimensional mechanisms that they can exert in physiological and pathological conditions. In this review, we discuss the multiverse of the molecular functions of asRNAs, describing their action through transcription-dependent and RNA-dependent mechanisms. Then, we report the workflow and methodologies to study and functionally characterize single asRNA candidates.
Language	English
Publishing date	2022-10-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2813993-8
ISSN	2311-553X ; 2311-553X
ISSN (online)	2311-553X
ISSN	2311-553X
DOI	10.3390/ncrna8060074
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Article ; Online: On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation.

Pagani, Giulia / Gohlke, Holger

Scientific reports

2018 Volume 8, Issue 1, Page(s) 5733

Abstract: Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether ... ...

Abstract	Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential TMD association has remained elusive. Here, we show by molecular dynamics simulations and association free energy calculations on TMDs of integrin α
MeSH term(s)	Amino Acid Sequence ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; Humans ; Integrins/agonists ; Integrins/chemistry ; Integrins/metabolism ; Molecular Dynamics Simulation ; Protein Binding ; Protein Conformation ; Protein Domains ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Subunits/chemistry ; Protein Subunits/metabolism ; Structure-Activity Relationship ; Thermodynamics
Chemical Substances	Integrins ; Protein Subunits
Language	English
Publishing date	2018-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-23778-5
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Article: MIR205HG

Bezzecchi, Eugenia / Pagani, Giulia / Forte, Barbara / Percio, Stefano / Zaffaroni, Nadia / Dolfini, Diletta / Gandellini, Paolo

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 909097

Abstract: Aside serving as host gene ... ...

Abstract	Aside serving as host gene for
Language	English
Publishing date	2022-06-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.909097
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Article ; Online: The pancancer overexpressed NFYC Antisense 1 controls cell cycle mitotic progression through in cis and in trans modes of action.

Pandini, Cecilia / Pagani, Giulia / Tassinari, Martina / Vitale, Emanuele / Bezzecchi, Eugenia / Saadeldin, Mona Kamal / Doldi, Valentina / Giannuzzi, Giuliana / Mantovani, Roberto / Chiara, Matteo / Ciarrocchi, Alessia / Gandellini, Paolo

Cell death & disease

2024 Volume 15, Issue 3, Page(s) 206

Abstract: Antisense RNAs (asRNAs) represent an underappreciated yet crucial layer of gene expression regulation. Generally thought to modulate their sense genes in cis through sequence complementarity or their act of transcription, asRNAs can also regulate ... ...

Abstract	Antisense RNAs (asRNAs) represent an underappreciated yet crucial layer of gene expression regulation. Generally thought to modulate their sense genes in cis through sequence complementarity or their act of transcription, asRNAs can also regulate different molecular targets in trans, in the nucleus or in the cytoplasm. Here, we performed an in-depth molecular characterization of NFYC Antisense 1 (NFYC-AS1), the asRNA transcribed head-to-head to NFYC subunit of the proliferation-associated NF-Y transcription factor. Our results show that NFYC-AS1 is a prevalently nuclear asRNA peaking early in the cell cycle. Comparative genomics suggests a narrow phylogenetic distribution, with a probable origin in the common ancestor of mammalian lineages. NFYC-AS1 is overexpressed pancancer, preferentially in association with RB1 mutations. Knockdown of NFYC-AS1 by antisense oligonucleotides impairs cell growth in lung squamous cell carcinoma and small cell lung cancer cells, a phenotype recapitulated by CRISPR/Cas9-deletion of its transcription start site. Surprisingly, expression of the sense gene is affected only when endogenous transcription of NFYC-AS1 is manipulated. This suggests that regulation of cell proliferation is at least in part independent of the in cis transcription-mediated effect on NFYC and is possibly exerted by RNA-dependent in trans effects converging on the regulation of G2/M cell cycle phase genes. Accordingly, NFYC-AS1-depleted cells are stuck in mitosis, indicating defects in mitotic progression. Overall, NFYC-AS1 emerged as a cell cycle-regulating asRNA with dual action, holding therapeutic potential in different cancer types, including the very aggressive RB1-mutated tumors.
MeSH term(s)	Animals ; Humans ; Phylogeny ; Gene Expression Regulation, Neoplastic ; RNA, Antisense/genetics ; Cell Cycle/genetics ; Cell Proliferation/genetics ; Lung Neoplasms/genetics ; RNA, Long Noncoding/genetics ; Cell Line, Tumor ; Cell Movement ; Mammals/genetics ; CCAAT-Binding Factor/genetics
Chemical Substances	RNA, Antisense ; RNA, Long Noncoding ; NFYC protein, human ; CCAAT-Binding Factor
Language	English
Publishing date	2024-03-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-024-06576-y
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Book ; Online ; Thesis: Linking structure and dynamics of integrin αIIbβ3 to its biological function via molecular dynamics simulations and free energy calculations

Pagani, Giulia [Verfasser] / Gohlke, Holger [Gutachter] / Strodel, Birgit [Gutachter]

2018

Author's details	giulia pagani ; Gutachter: Holger Gohlke, Birgit Strodel
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	English
Publisher	Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
Publishing place	Düsseldorf
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: The human platelet antigen-1b (Pro

Pagani, Giulia / Pereira, Joana P V / Stoldt, Volker R / Beck, Andreas / Scharf, Rüdiger E / Gohlke, Holger

The Journal of biological chemistry

2018 Volume 293, Issue 13, Page(s) 4830–4844

Abstract: Integrins are heterodimeric cell-adhesion receptors comprising α and β subunits that transmit signals allosterically in both directions across the membrane by binding to intra- and extracellular components. The human platelet antigen-1 (HPA-1) ... ...

Abstract	Integrins are heterodimeric cell-adhesion receptors comprising α and β subunits that transmit signals allosterically in both directions across the membrane by binding to intra- and extracellular components. The human platelet antigen-1 (HPA-1) polymorphism in α
MeSH term(s)	Allosteric Regulation ; Antigens, Human Platelet/genetics ; Antigens, Human Platelet/metabolism ; Blood Platelets/metabolism ; Blood Platelets/pathology ; HEK293 Cells ; Humans ; Platelet Aggregation ; Platelet Glycoprotein GPIIb-IIIa Complex/genetics ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; Signal Transduction ; Thrombosis/genetics ; Thrombosis/metabolism ; Thrombosis/pathology
Chemical Substances	Antigens, Human Platelet ; ITGB3 protein, human ; Platelet Glycoprotein GPIIb-IIIa Complex ; human platelet antigen 1b
Language	English
Publishing date	2018-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA118.002149
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Uc I Zs.108: Show issues

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Article ; Online: Asthma-protective agents in dust from traditional farm environments.

Marques Dos Santos, Mauricius / Pivniouk, Vadim / Rankl, Bettina / Walker, Alesia / Pagani, Giulia / Hertkorn, Norbert / Schmitt-Kopplin, Philippe / Müller, Christoph / Bracher, Franz / Merl-Pham, Juliane / Hauck, Stefanie M / Schloter, Michael / Michael, Ashley N / Anderson, Dayna / Honeker, Linnea / Gozdz, Justyna / Pivniouk, Oksana / Ober, Carole / Holbreich, Mark /

Martinez, Fernando D / Snyder, Shane A / von Mutius, Erika / Vercelli, Donata

The Journal of allergy and clinical immunology

2023 Volume 152, Issue 3, Page(s) 610–621

Abstract: Background: Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma ... ...

Abstract	Background: Growing up on traditional European or US Amish dairy farms in close contact with cows and hay protects children against asthma, and airway administration of extracts from dust collected from cowsheds of those farms prevents allergic asthma in mice. Objectives: This study sought to begin identifying farm-derived asthma-protective agents. Methods: Our work unfolded along 2 unbiased and independent but complementary discovery paths. Dust extracts (DEs) from protective and nonprotective farms (European and Amish cowsheds vs European sheep sheds) were analyzed by comparative nuclear magnetic resonance profiling and differential proteomics. Bioactivity-guided size fractionation focused on protective Amish cowshed DEs. Multiple in vitro and in vivo functional assays were used in both paths. Some of the proteins thus identified were characterized by in-solution and in-gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis enzymatic digestion/peptide mapping followed by liquid chromatography/mass spectrometry. The cargo carried by these proteins was analyzed by untargeted liquid chromatography-high-resolution mass spectrometry. Results: Twelve carrier proteins of animal and plant origin, including the bovine lipocalins Bos d 2 and odorant binding protein, were enriched in DEs from protective European cowsheds. A potent asthma-protective fraction of Amish cowshed DEs (≈0.5% of the total carbon content of unfractionated extracts) contained 7 animal and plant proteins, including Bos d 2 and odorant binding protein loaded with fatty acid metabolites from plants, bacteria, and fungi. Conclusions: Animals and plants from traditional farms produce proteins that transport hydrophobic microbial and plant metabolites. When delivered to mucosal surfaces, these agents might regulate airway responses.
MeSH term(s)	Female ; Animals ; Cattle ; Mice ; Sheep ; Farms ; Dust/analysis ; Asthma/prevention & control ; Allergens ; Respiratory System
Chemical Substances	Dust ; Allergens
Language	English
Publishing date	2023-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2023.05.013
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Article ; Online: Excessive Unbalanced Meat Consumption in the First Year of Life Increases Asthma Risk in the PASTURE and LUKAS2 Birth Cohorts.

Hose, Alexander J / Pagani, Giulia / Karvonen, Anne M / Kirjavainen, Pirkka V / Roduit, Caroline / Genuneit, Jon / Schmaußer-Hechfellner, Elisabeth / Depner, Martin / Frei, Remo / Lauener, Roger / Riedler, Josef / Schaub, Bianca / Fuchs, Oliver / von Mutius, Erika / Divaret-Chauveau, Amandine / Pekkanen, Juha / Ege, Markus J

Frontiers in immunology

2021 Volume 12, Page(s) 651709

Abstract: A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate ... ...

Abstract	A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate them to asthma risk at school age. PASTURE (N=1133) and LUKAS2 (N=228) are prospective birth cohort studies designed to evaluate protective and risk factors for atopic diseases, including dietary patterns. Feeding practices were reported by parents in monthly diaries between the 4
MeSH term(s)	Animals ; Asthma/epidemiology ; Asthma/immunology ; Asthma/microbiology ; Child ; Child, Preschool ; DNA, Bacterial/isolation & purification ; Diet Records ; Europe/epidemiology ; Feeding Behavior ; Female ; Follow-Up Studies ; Gastrointestinal Microbiome/genetics ; Gastrointestinal Microbiome/immunology ; Humans ; Infant ; Infant Nutritional Physiological Phenomena/immunology ; Infant, Newborn ; Male ; Meat/adverse effects ; Prevalence ; Prospective Studies ; RNA, Ribosomal, 16S/genetics ; Risk Assessment/statistics & numerical data
Chemical Substances	DNA, Bacterial ; RNA, Ribosomal, 16S
Language	English
Publishing date	2021-04-27
Publishing country	Switzerland
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.651709
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Article ; Online: Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release.

Donner, Lili / Fälker, Knut / Gremer, Lothar / Klinker, Stefan / Pagani, Giulia / Ljungberg, Liza U / Lothmann, Kimberley / Rizzi, Federica / Schaller, Martin / Gohlke, Holger / Willbold, Dieter / Grenegard, Magnus / Elvers, Margitta

Science signaling

2016 Volume 9, Issue 429, Page(s) ra52

Abstract: Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-β (Aβ) in the walls of cerebral vessels. CAA and Aβ deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We ... ...

Abstract	Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-β (Aβ) in the walls of cerebral vessels. CAA and Aβ deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We investigated the contribution of platelets, which accumulate at vascular Aβ deposits, to CAA. We found that synthetic monomeric Aβ40 bound through its RHDS (Arg-His-Asp-Ser) sequence to integrin αIIbβ3, which is the receptor for the extracellular matrix protein fibrinogen, and stimulated the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets. Clusterin promoted the formation of fibrillar Aβ aggregates, and ADP acted through its receptors P2Y1 and P2Y12 on platelets to enhance integrin αIIbβ3 activation, further increasing the secretion of clusterin and Aβ40 binding to platelets. Platelets from patients with Glanzmann's thrombasthenia, a bleeding disorder in which platelets have little or dysfunctional αIIbβ3, indicated that the abundance of this integrin dictated Aβ-induced clusterin release and platelet-induced Aβ aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited Aβ aggregation in platelet cultures; in transgenic AD model mice, this drug reduced the amount of clusterin in the circulation and the incidence of CAA. Our findings indicate that activated platelets directly contribute to CAA by promoting the formation of Aβ aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients.
MeSH term(s)	Adolescent ; Adult ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Blood Platelets/cytology ; Brain/metabolism ; Cerebrovascular Circulation ; Clusterin/metabolism ; Crosses, Genetic ; Disease Progression ; Female ; Fibrinogen/metabolism ; Genotype ; Humans ; Integrin alpha2/metabolism ; Integrins/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Molecular Dynamics Simulation ; Phosphorylation ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; Signal Transduction ; Young Adult
Chemical Substances	Amyloid beta-Peptides ; CLU protein, human ; Clu protein, mouse ; Clusterin ; ITGA2B protein, human ; Integrin alpha2 ; Integrins ; Platelet Glycoprotein GPIIb-IIIa Complex ; Fibrinogen (9001-32-5)
Language	English
Publishing date	2016-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aaf6240
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