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Article ; Online: Transcriptional Landscape of CUT-Class Homeobox Genes in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Nagel, Stefan / Rand, Ulfert / Pommerenke, Claudia / Meyer, Corinna

International journal of molecular sciences

2024 Volume 25, Issue 5

Abstract: Homeobox genes encode developmental transcription factors regulating tissue-specific differentiation processes and drive cancerogenesis when deregulated. Dendritic cells (DCs) are myeloid immune cells occurring as two types, either conventional or ... ...

Abstract	Homeobox genes encode developmental transcription factors regulating tissue-specific differentiation processes and drive cancerogenesis when deregulated. Dendritic cells (DCs) are myeloid immune cells occurring as two types, either conventional or plasmacytoid DCs. Recently, we showed that the expression of NKL-subclass homeobox gene VENTX is restricted to conventional DCs, regulating developmental genes. Here, we identified and investigated homeobox genes specifically expressed in plasmacytoid DCs (pDCs) and derived blastic plasmacytoid dendritic cell neoplasm (BPDCN). We analyzed gene expression data, performed RQ-PCR, protein analyses by Western blot and immuno-cytology, siRNA-mediated knockdown assays and subsequent RNA-sequencing and live-cell imaging. Screening of public gene expression data revealed restricted activity of the CUT-class homeobox gene CUX2 in pDCs. An extended analysis of this homeobox gene class in myelopoiesis showed that additional CUX2 activity was restricted to myeloid progenitors, while BPDCN patients aberrantly expressed ONECUT2, which remained silent in the complete myeloid compartment. ONECUT2 expressing BPDCN cell line CAL-1 served as a model to investigate its regulation and oncogenic activity. The ONECUT2 locus at 18q21 was duplicated and activated by IRF4, AUTS2 and TNF-signaling and repressed by BMP4-, TGFb- and IL13-signalling. Functional analyses of ONECUT2 revealed the inhibition of pDC differentiation and of CDKN1C and CASP1 expression, while SMAD3 and EPAS1 were activated. EPAS1 in turn enhanced survival under hypoxic conditions which thus may support dendritic tumor cells residing in hypoxic skin lesions. Collectively, we revealed physiological and aberrant activities of CUT-class homeobox genes in myelopoiesis including pDCs and in BPDCN, respectively. Our data may aid in the diagnosis of BPDCN patients and reveal novel therapeutic targets for this fatal malignancy.
MeSH term(s)	Humans ; Genes, Homeobox ; Cell Differentiation ; Cell Line ; Myeloid Cells/metabolism ; Dendritic Cells/metabolism ; Hematologic Neoplasms/pathology ; Transcription Factors/metabolism ; Homeodomain Proteins/genetics
Chemical Substances	ONECUT2 protein, human ; Transcription Factors ; Homeodomain Proteins
Language	English
Publishing date	2024-02-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25052764
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Foscarnet-Type Inorganic-Organic Hybrid Nanoparticles for Effective Antiviral Therapy.

Khorenko, Mikhail / Rand, Ulfert / Cicin-Sain, Luka / Feldmann, Claus

ACS biomaterials science & engineering

2022 Volume 8, Issue 4, Page(s) 1596–1603

Abstract: ZrO] ...

Abstract	[ZrO]
MeSH term(s)	Antiviral Agents/pharmacology ; Cytomegalovirus/genetics ; Foscarnet/pharmacology ; Herpesvirus 1, Human/genetics ; Humans ; Nanoparticles/therapeutic use
Chemical Substances	Antiviral Agents ; Foscarnet (364P9RVW4X)
Language	English
Publishing date	2022-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2373-9878
ISSN (online)	2373-9878
DOI	10.1021/acsbiomaterials.2c00074
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Article ; Online: Fibroblasts are a site of murine cytomegalovirus lytic replication and Stat1-dependent latent persistence in vivo.

Sitnik, Katarzyna M / Krstanović, Fran / Gödecke, Natascha / Rand, Ulfert / Kubsch, Tobias / Maaß, Henrike / Kim, Yeonsu / Brizić, Ilija / Čičin-Šain, Luka

Nature communications

2023 Volume 14, Issue 1, Page(s) 3087

Abstract: To date, no herpesvirus has been shown to latently persist in fibroblastic cells. Here, we show that murine cytomegalovirus, a β-herpesvirus, persists for the long term and across organs in PDGFRα-positive fibroblastic cells, with similar or higher ... ...

Abstract	To date, no herpesvirus has been shown to latently persist in fibroblastic cells. Here, we show that murine cytomegalovirus, a β-herpesvirus, persists for the long term and across organs in PDGFRα-positive fibroblastic cells, with similar or higher genome loads than in the previously known sites of murine cytomegalovirus latency. Whereas murine cytomegalovirus gene transcription in PDGFRα-positive fibroblastic cells is almost completely silenced at 5 months post-infection, these cells give rise to reactivated virus ex vivo, arguing that they support latent murine cytomegalovirus infection. Notably, PDGFRα-positive fibroblastic cells also support productive virus replication during primary murine cytomegalovirus infection. Mechanistically, Stat1-deficiency promotes lytic infection but abolishes latent persistence of murine cytomegalovirus in PDGFRα-positive fibroblastic cells in vivo. In sum, fibroblastic cells have a dual role as a site of lytic murine cytomegalovirus replication and a reservoir of latent murine cytomegalovirus in vivo and STAT1 is required for murine cytomegalovirus latent persistence in vivo.
MeSH term(s)	Animals ; Mice ; Cytomegalovirus/genetics ; Cytomegalovirus Infections ; Muromegalovirus ; Virus Latency/genetics ; Receptor, Platelet-Derived Growth Factor alpha ; Virus Replication ; Fibroblasts ; STAT1 Transcription Factor/genetics
Chemical Substances	Receptor, Platelet-Derived Growth Factor alpha (EC 2.7.10.1) ; Stat1 protein, mouse ; STAT1 Transcription Factor
Language	English
Publishing date	2023-05-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38449-x
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Article ; Online: Pharmacological modulators of epithelial immunity uncovered by synthetic genetic tracing of SARS-CoV-2 infection responses.

Jiang, Ben / Schmitt, Matthias Jürgen / Rand, Ulfert / Company, Carlos / Dramaretska, Yuliia / Grossmann, Melanie / Serresi, Michela / Čičin-Šain, Luka / Gargiulo, Gaetano

Science advances

2023 Volume 9, Issue 25, Page(s) eadf4975

Abstract: Epithelial immune responses govern tissue homeostasis and offer drug targets against maladaptation. Here, we report a framework to generate drug discovery-ready reporters of cellular responses to viral infection. We reverse-engineered epithelial cell ... ...

Abstract	Epithelial immune responses govern tissue homeostasis and offer drug targets against maladaptation. Here, we report a framework to generate drug discovery-ready reporters of cellular responses to viral infection. We reverse-engineered epithelial cell responses to SARS-CoV-2, the viral agent fueling the ongoing COVID-19 pandemic, and designed synthetic transcriptional reporters whose molecular logic comprises interferon-α/β/γ and NF-κB pathways. Such regulatory potential reflected single-cell data from experimental models to severe COVID-19 patient epithelial cells infected by SARS-CoV-2. SARS-CoV-2, type I interferons, and RIG-I drive reporter activation. Live-cell image-based phenotypic drug screens identified JAK inhibitors and DNA damage inducers as antagonistic modulators of epithelial cell response to interferons, RIG-I stimulation, and SARS-CoV-2. Synergistic or antagonistic modulation of the reporter by drugs underscored their mechanism of action and convergence on endogenous transcriptional programs. Our study describes a tool for dissecting antiviral responses to infection and sterile cues and rapidly discovering rational drug combinations for emerging viruses of concern.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Pandemics ; Interferon Type I ; Epithelial Cells
Chemical Substances	Interferon Type I
Language	English
Publishing date	2023-06-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adf4975
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Article ; Online: A Novel Triple-Fluorescent HCMV Strain Reveals Gene Expression Dynamics and Anti-Herpesviral Drug Mechanisms.

Rand, Ulfert / Kubsch, Tobias / Kasmapour, Bahram / Cicin-Sain, Luka

Frontiers in cellular and infection microbiology

2021 Volume 10, Page(s) 536150

Abstract: Human Cytomegalovirus (HCMV) infection may result in severe outcomes in immunocompromised individuals such as AIDS patients, transplant recipients, and neonates. To date, no vaccines are available and there are only few drugs for anti-HCMV therapy. ... ...

Abstract	Human Cytomegalovirus (HCMV) infection may result in severe outcomes in immunocompromised individuals such as AIDS patients, transplant recipients, and neonates. To date, no vaccines are available and there are only few drugs for anti-HCMV therapy. Adverse effects and the continuous emergence of drug-resistance strains require the identification of new drug candidates in the near future. Identification and characterization of such compounds and biological factors requires sensitive and reliable detection techniques of HCMV infection, gene expression and spread. In this work, we present and validate a novel concept for multi-reporter herpesviruses, identified through iterative testing of minimally invasive mutations. We integrated up to three fluorescence reporter genes into replication-competent HCMV strains, generating reporter HCMVs that allow the visualization of replication cycle stages of HCMV, namely the immediate early (IE), early (E), and late (L) phase. Fluorescent proteins with clearly distinguishable emission spectra were linked by 2A peptides to essential viral genes, allowing bicistronic expression of the viral and the fluorescent protein without major effects on viral fitness. By using this triple color reporter HCMV, we monitored gene expression dynamics of the IE, E, and L genes by measuring the fluorescent signal of the viral gene-associated fluorophores within infected cell populations and at high temporal resolution. We demonstrate distinct inhibitory profiles of foscarnet, fomivirsen, phosphonoacetic acid, ganciclovir, and letermovir reflecting their mode-of-action. In conclusion, our data argues that this experimental approach allows the identification and characterization of new drug candidates in a single step.
MeSH term(s)	Antiviral Agents/pharmacology ; Cytomegalovirus/genetics ; Gene Expression ; Herpesviridae ; Humans ; Infant, Newborn ; Pharmaceutical Preparations ; Virus Replication
Chemical Substances	Antiviral Agents ; Pharmaceutical Preparations
Language	English
Publishing date	2021-01-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2020.536150
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Article ; Online: Fibroblasts are a site of murine cytomegalovirus lytic replication and Stat1-dependent latent persistence in vivo

Katarzyna M. Sitnik / Fran Krstanović / Natascha Gödecke / Ulfert Rand / Tobias Kubsch / Henrike Maaß / Yeonsu Kim / Ilija Brizić / Luka Čičin-Šain

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 13

Abstract: Abstract To date, no herpesvirus has been shown to latently persist in fibroblastic cells. Here, we show that murine cytomegalovirus, a β-herpesvirus, persists for the long term and across organs in PDGFRα-positive fibroblastic cells, with similar or ... ...

Abstract	Abstract To date, no herpesvirus has been shown to latently persist in fibroblastic cells. Here, we show that murine cytomegalovirus, a β-herpesvirus, persists for the long term and across organs in PDGFRα-positive fibroblastic cells, with similar or higher genome loads than in the previously known sites of murine cytomegalovirus latency. Whereas murine cytomegalovirus gene transcription in PDGFRα-positive fibroblastic cells is almost completely silenced at 5 months post-infection, these cells give rise to reactivated virus ex vivo, arguing that they support latent murine cytomegalovirus infection. Notably, PDGFRα-positive fibroblastic cells also support productive virus replication during primary murine cytomegalovirus infection. Mechanistically, Stat1-deficiency promotes lytic infection but abolishes latent persistence of murine cytomegalovirus in PDGFRα-positive fibroblastic cells in vivo. In sum, fibroblastic cells have a dual role as a site of lytic murine cytomegalovirus replication and a reservoir of latent murine cytomegalovirus in vivo and STAT1 is required for murine cytomegalovirus latent persistence in vivo.
Keywords	Science ; Q
Subject code	570
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Persicamidines-Unprecedented Sesquarterpenoids with Potent Antiviral Bioactivity against Coronaviruses.

Keller, Lena / Oueis, Emilia / Kaur, Amninder / Safaei, Nasim / Kirsch, Susanne H / Gunesch, Antonia P / Haid, Sibylle / Rand, Ulfert / Čičin-Šain, Luka / Fu, Chengzhang / Wink, Joachim / Pietschmann, Thomas / Müller, Rolf

Angewandte Chemie (International ed. in English)

2023 Volume 62, Issue 6, Page(s) e202214595

Abstract: A new family of highly unusual sesquarterpenoids (persicamidines A-E) exhibiting significant antiviral activity was isolated from a newly discovered actinobacterial strain, Kibdelosporangium persicum sp. nov., collected from a hot desert in Iran. ... ...

Abstract	A new family of highly unusual sesquarterpenoids (persicamidines A-E) exhibiting significant antiviral activity was isolated from a newly discovered actinobacterial strain, Kibdelosporangium persicum sp. nov., collected from a hot desert in Iran. Extensive NMR analysis unraveled a hexacyclic terpenoid molecule with a modified sugar moiety on one side and a highly unusual isourea moiety fused to the terpenoid structure. The structures of the five analogues differed only in the aminoalkyl side chain attached to the isourea moiety. Persicamidines A-E showed potent activity against hCoV-229E and SARS-CoV-2 viruses in the nanomolar range together with very good selectivity indices, making persicamidines promising as starting points for drug development.
MeSH term(s)	Humans ; Antiviral Agents/chemistry ; COVID-19 ; SARS-CoV-2 ; Coronavirus 229E, Human ; Plant Extracts
Chemical Substances	Antiviral Agents ; Plant Extracts
Language	English
Publishing date	2023-01-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202214595
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Article ; Online: A universal microfluidic approach for integrated analysis of temporal homocellular and heterocellular signaling and migration dynamics.

Yang, Haowen / Sinha, Nidhi / Rand, Ulfert / Hauser, Hansjörg / Köster, Mario / de Greef, Tom F A / Tel, Jurjen

Biosensors & bioelectronics

2022 Volume 211, Page(s) 114353

Abstract: Microfluidics offers precise and dynamic control of microenvironments for the study of temporal cellular responses. However, recent research focusing solely on either homocellular (single-cell, population) or heterocellular response may yield ... ...

Abstract	Microfluidics offers precise and dynamic control of microenvironments for the study of temporal cellular responses. However, recent research focusing solely on either homocellular (single-cell, population) or heterocellular response may yield insufficient output, which possibly leads to partial comprehension about the underlying mechanisms of signaling events and corresponding cellular behaviors. Here, a universal microfluidic approach is developed for integrated analysis of temporal signaling and cell migration dynamics in multiple cellular contexts (single-cell, population and coculture). This approach allows to confine the desired number or mixture of specific cell sample types in a single device. Precise single cell seeding was achieved manually with bidirectional controllability. Coupled with time-lapse imaging, temporal cellular responses can be observed with single-cell resolution. Using NIH3T3 cells stably expressing signal transducer and activator of transcription 1/2 (STAT1/2) activity biosensors, temporal STAT1/2 activation and cell migration dynamics were explored in isolated single cells, populations and cocultures stimulated with temporal inputs, such as single-pulse and continuous signals of interferon γ (IFNγ) or lipopolysaccharide (LPS). We demonstrate distinct dynamic responses of fibroblasts in different cellular contexts. Our presented approach facilitates a multi-dimensional understanding of STAT signaling and corresponding migration behaviors.
MeSH term(s)	Animals ; Biosensing Techniques ; Cell Movement ; Mice ; Microfluidics/methods ; NIH 3T3 Cells ; Signal Transduction
Language	English
Publishing date	2022-05-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1011023-9
ISSN	1873-4235 ; 0956-5663
ISSN (online)	1873-4235
ISSN	0956-5663
DOI	10.1016/j.bios.2022.114353
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Article: A universal microfluidic approach for integrated analysis of temporal homocellular and heterocellular signaling and migration dynamics

Yang, Haowen / Sinha, Nidhi / Rand, Ulfert / Hauser, Hansjörg / Köster, Mario / de Greef, Tom F.A. / Tel, Jurjen

Biosensors & bioelectronics. 2022 Sept. 01, v. 211

2022

Abstract	Microfluidics offers precise and dynamic control of microenvironments for the study of temporal cellular responses. However, recent research focusing solely on either homocellular (single-cell, population) or heterocellular response may yield insufficient output, which possibly leads to partial comprehension about the underlying mechanisms of signaling events and corresponding cellular behaviors. Here, a universal microfluidic approach is developed for integrated analysis of temporal signaling and cell migration dynamics in multiple cellular contexts (single-cell, population and coculture). This approach allows to confine the desired number or mixture of specific cell sample types in a single device. Precise single cell seeding was achieved manually with bidirectional controllability. Coupled with time-lapse imaging, temporal cellular responses can be observed with single-cell resolution. Using NIH3T3 cells stably expressing signal transducer and activator of transcription 1/2 (STAT1/2) activity biosensors, temporal STAT1/2 activation and cell migration dynamics were explored in isolated single cells, populations and cocultures stimulated with temporal inputs, such as single-pulse and continuous signals of interferon γ (IFNγ) or lipopolysaccharide (LPS). We demonstrate distinct dynamic responses of fibroblasts in different cellular contexts. Our presented approach facilitates a multi-dimensional understanding of STAT signaling and corresponding migration behaviors.
Keywords	biosensors ; cell movement ; coculture ; fibroblasts ; lipopolysaccharides ; microfluidic technology ; signal transduction ; transactivators
Language	English
Dates of publication	2022-0901
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1011023-9
ISSN	1873-4235 ; 0956-5663
ISSN (online)	1873-4235
ISSN	0956-5663
DOI	10.1016/j.bios.2022.114353
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Article ; Online: A Novel Triple-Fluorescent HCMV Strain Reveals Gene Expression Dynamics and Anti-Herpesviral Drug Mechanisms.

Rand, Ulfert / Kubsch, Tobias / Kasmapour, Bahram / Cicin-Sain, Luka

10 ; 536150 ; Frontiers in cellular and infection microbiology ; Switzerland

2021

Abstract	Human Cytomegalovirus (HCMV) infection may result in severe outcomes in immunocompromised individuals such as AIDS patients, transplant recipients, and neonates. To date, no vaccines are available and there are only few drugs for anti-HCMV therapy. Adverse effects and the continuous emergence of drug-resistance strains require the identification of new drug candidates in the near future. Identification and characterization of such compounds and biological factors requires sensitive and reliable detection techniques of HCMV infection, gene expression and spread. In this work, we present and validate a novel concept for multi-reporter herpesviruses, identified through iterative testing of minimally invasive mutations. We integrated up to three fluorescence reporter genes into replication-competent HCMV strains, generating reporter HCMVs that allow the visualization of replication cycle stages of HCMV, namely the immediate early (IE), early (E), and late (L) phase. Fluorescent proteins with clearly distinguishable emission spectra were linked by 2A peptides to essential viral genes, allowing bicistronic expression of the viral and the fluorescent protein without major effects on viral fitness. By using this triple color reporter HCMV, we monitored gene expression dynamics of the IE, E, and L genes by measuring the fluorescent signal of the viral gene-associated fluorophores within infected cell populations and at high temporal resolution. We demonstrate distinct inhibitory profiles of foscarnet, fomivirsen, phosphonoacetic acid, ganciclovir, and letermovir reflecting their mode-of-action. In conclusion, our data argues that this experimental approach allows the identification and characterization of new drug candidates in a single step.
Keywords	Human Cytomegalovirus ; antivirals ; herpesvirus ; in vitro drug testing ; letermovir ; live-cell imaging ; reporter assay ; screening
Subject code	570
Language	English
Publishing date	2021-01-08
Publisher	Frontiers
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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