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Article ; Online: A form of inherited hyperferritinemia associated with bi-allelic pathogenic variants of STAB1.

Monfrini, Edoardo / Pelucchi, Sara / Hollmén, Maija / Viitala, Miro / Mariani, Raffaella / Bertola, Francesca / Majore, Silvia / Di Fonzo, Alessio / Piperno, Alberto

American journal of human genetics

2023 Volume 110, Issue 8, Page(s) 1436–1443

Abstract: Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of ...

Abstract	Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and flow cytometry assays were performed on liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. Through a combined approach of whole-exome sequencing and homozygosity mapping, we found bi-allelic STAB1 variants in ten subjects from seven families. STAB1 encodes the multifunctional scavenger receptor stabilin-1. Immunohistochemistry and flow cytometry analyses showed absent or markedly reduced stabilin-1 in liver samples, monocytes, and monocyte-derived macrophages. Our findings show a strong association between otherwise unexplained hyperferritinemia and bi-allelic STAB1 mutations suggesting the existence of another genetic cause of hyperferritinemia without iron overload and an unexpected function of stabilin-1 in ferritin metabolism.
MeSH term(s)	Humans ; Hyperferritinemia ; Iron Overload/genetics ; Iron Overload/diagnosis ; Ferritins/genetics ; Macrophages ; Alleles
Chemical Substances	Ferritins (9007-73-2)
Language	English
Publishing date	2023-07-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2023.07.004
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Article: Immunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8

Viitala, Miro / Virtakoivu, Reetta / Tadayon, Sina / Rannikko, Jenna / Jalkanen, Sirpa / Hollmén, Maija

Clinical cancer research : an official journal of the American Association for Cancer Research

2019 Volume 25, Issue 11, Page(s) 3289–3303

Abstract: Purpose: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in ... ...

Abstract	Purpose: As foremost regulators of cancer-related inflammation and immunotherapeutic resistance, tumor-associated macrophages have garnered major interest as immunotherapeutic drug targets. However, depletory strategies have yielded little benefit in clinical studies to date. An alternative approach is to exploit macrophage plasticity and "reeducate" tumorigenic macrophages toward an immunostimulatory phenotype to activate the host's antitumor immunity. Results: Genetic deficiency of macrophage Clever-1 markedly impaired solid tumor growth. This effect was mediated by macrophages that became immunostimulatory in the absence of Clever-1, skewing the suppressive tumor microenvironment toward inflammation and activating endogenous antitumor CD8 Conclusions: These findings demonstrate the importance of macrophages in mediating antitumor immune responses and support the clinical evaluation of immunotherapeutic Clever-1 blockade as a novel cancer treatment strategy.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/immunology ; Immunotherapy ; Macrophages/drug effects ; Mice ; Neoplasms ; Tumor Microenvironment/drug effects
Language	English
Publishing date	2019-02-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-18-3016
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Article: High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer.

Ketola, Kirsi / Viitala, Miro / Kohonen, Pekka / Fey, Vidal / Culig, Zoran / Kallioniemi, Olli / Iljin, Kristiina

Journal of molecular biochemistry

2016 Volume 5, Issue 1, Page(s) 12–22

Abstract: Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer ...

Abstract	Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer cells. The effect of compounds on cell viability was compared in androgen ablated LNCaP prostate cancer cells and in LNCaP cells grown in presence of androgens as well as in two non-malignant prostate epithelial cells (RWPE-1 and EP156T). Validation experiments of cancer specific anti-proliferative compounds indicated pinosylvin methyl ether (PSME) and tanshinone IIA as potent inhibitors of androgen ablated LNCaP cell proliferation. PSME is a stilbene compound with no previously described anti-neoplastic activity whereas tanshinone IIA is currently used in cardiovascular disorders and proposed as a cancer drug. To gain insights into growth inhibitory mechanisms in CRPC, genome-wide gene expression analysis was performed in PSME- and tanshinone IIA-exposed cells. Both compounds altered the expression of genes involved in cell cycle and steroid and cholesterol biosynthesis in androgen ablated LNCaP cells. Decrease in androgen signalling was confirmed by reduced expression of androgen receptor and prostate specific antigen in PSME- or tanshinone IIA-exposed cells. Taken together, this systematic screen identified a novel anti-proliferative agent, PSME, for CRPC. Moreover, our screen confirmed tanshinone IIA as well as several other compounds as potential prostate cancer growth inhibitors also in androgen ablated prostate cancer cells. These results provide valuable starting points for preclinical and clinical studies for CRPC treatment.
Language	English
Publishing date	2016-11-07
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2659848-6
ISSN	2241-0090
ISSN	2241-0090
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Article ; Online: Enhanced Antibody Production in Clever-1/Stabilin-1-Deficient Mice.

Dunkel, Johannes / Viitala, Miro / Karikoski, Marika / Rantakari, Pia / Virtakoivu, Reetta / Elima, Kati / Hollmén, Maija / Jalkanen, Sirpa / Salmi, Marko

Frontiers in immunology

2018 Volume 9, Page(s) 2257

Abstract: Clever-1, encoded by ... ...

Abstract	Clever-1, encoded by the
MeSH term(s)	Animals ; Antibody Formation/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Adhesion Molecules, Neuronal/deficiency ; Cell Adhesion Molecules, Neuronal/genetics ; Cell Adhesion Molecules, Neuronal/immunology ; Coculture Techniques ; Immunoglobulin M/immunology ; Immunoglobulin M/metabolism ; Macrophages/cytology ; Macrophages/immunology ; Macrophages/metabolism ; Mice, Knockout ; Monocytes/cytology ; Monocytes/immunology ; Monocytes/metabolism ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/immunology ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Cell Adhesion Molecules, Neuronal ; Immunoglobulin M ; Stab1 protein, mouse ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2018-10-08
Publishing country	Switzerland
Document type	Journal Article ; 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.2018.02257
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Article ; Online: Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E

Rinne, Petteri / Kadiri, James J / Velasco-Delgado, Mauricio / Nuutinen, Salla / Viitala, Miro / Hollmén, Maija / Rami, Martina / Savontaus, Eriika / Steffens, Sabine

Arteriosclerosis, thrombosis, and vascular biology

2017 Volume 38, Issue 2, Page(s) 313–323

Abstract: Objective: The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 ( ...

Abstract	Objective: The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Approach and results: Apoe Conclusions: The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation.
MeSH term(s)	ATP Binding Cassette Transporter 1/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 1/metabolism ; Animals ; Aorta/metabolism ; Aorta/pathology ; Aortic Diseases/genetics ; Aortic Diseases/metabolism ; Aortic Diseases/pathology ; Atherosclerosis/genetics ; Atherosclerosis/metabolism ; Atherosclerosis/pathology ; Cells, Cultured ; Cholesterol/metabolism ; Diet, High-Fat ; Disease Models, Animal ; Fatty Liver/genetics ; Fatty Liver/metabolism ; Fatty Liver/pathology ; Hypercholesterolemia/genetics ; Hypercholesterolemia/metabolism ; Hypercholesterolemia/pathology ; Macrophages/metabolism ; Macrophages/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; Monocytes/metabolism ; Monocytes/pathology ; Plaque, Atherosclerotic ; Receptor, Melanocortin, Type 1/deficiency ; Receptor, Melanocortin, Type 1/genetics
Chemical Substances	ABCA1 protein, mouse ; ABCG1 protein, mouse ; ATP Binding Cassette Transporter 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 1 ; Receptor, Melanocortin, Type 1 ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2017-12-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.117.310418
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Article ; Online: Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial.

Clinical cancer research : an official journal of the American Association for Cancer Research

2021 Volume 27, Issue 15, Page(s) 4205–4220

Abstract: Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel ... ...

Abstract	Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 Patients and methods: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8 Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.
MeSH term(s)	Humans ; CD8-Positive T-Lymphocytes/immunology ; Cell Adhesion Molecules, Neuronal/antagonists & inhibitors ; Down-Regulation ; Lymphocyte Activation/drug effects ; Neoplasms/drug therapy ; Neoplasms/immunology ; Receptors, Lymphocyte Homing/antagonists & inhibitors
Chemical Substances	Cell Adhesion Molecules, Neuronal ; Receptors, Lymphocyte Homing ; STAB1 protein, human ; bexmarilimab
Language	English
Publishing date	2021-06-02
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-4862
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Article ; Online: High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion.

Lehtinen, Laura / Ketola, Kirsi / Mäkelä, Rami / Mpindi, John-Patrick / Viitala, Miro / Kallioniemi, Olli / Iljin, Kristiina

Oncotarget

2013 Volume 4, Issue 1, Page(s) 48–63

Abstract: Vimentin is an intermediate filament protein, with a key role in the epithelial to mesenchymal transition as well as cell invasion, and it is often upregulated during cancer progression. However, relatively little is known about its regulation in cancer ... ...

Abstract	Vimentin is an intermediate filament protein, with a key role in the epithelial to mesenchymal transition as well as cell invasion, and it is often upregulated during cancer progression. However, relatively little is known about its regulation in cancer cells. Here, we performed an RNA interference screen followed by protein lysate microarray analysis in bone metastatic MDA-MB-231(SA) breast cancer cells to identify novel regulators of vimentin expression. Out of the 596 genes investigated, three novel vimentin regulators EPHB4, WIPF2 and MTHFD2 were identified. The reduced vimentin expression in response to EPHB4, WIPF2 and MTHFD2 silencing was observed at mRNA and protein levels. Bioinformatic analysis of gene expression data across cancers indicated overexpression of EPHB4 and MTHFD2 in breast cancer and high expression associated with poor clinical characteristics. Analysis of 96 cDNA samples derived from both normal and malignant human tissues suggested putative association with metastatic disease. MTHFD2 knockdown resulted in impaired cell migration and invasion into extracellular matrix as well as decreased the fraction of cells with a high CD44 expression, a marker of cancer stem cells. Furthermore, MTHFD2 expression was induced in response to TGF-β stimulation in breast cancer cells. Our results show that MTHFD2 is overexpressed in breast cancer, associates with poor clinical characteristics and promotes cellular features connected with metastatic disease, thus implicating MTHFD2 as a potential drug target to block breast cancer cell migration and invasion.
MeSH term(s)	Aminohydrolases/genetics ; Aminohydrolases/metabolism ; Antineoplastic Agents/pharmacology ; Blotting, Western ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cadherins/genetics ; Cadherins/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hyaluronan Receptors/genetics ; Hyaluronan Receptors/metabolism ; Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics ; Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism ; Microfilament Proteins ; Microscopy, Confocal ; Multienzyme Complexes/genetics ; Multienzyme Complexes/metabolism ; Neoplasm Invasiveness ; Neoplasm Metastasis ; RNA Interference ; Receptor, EphB4/genetics ; Receptor, EphB4/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transforming Growth Factor beta/pharmacology ; Vimentin/genetics ; Vimentin/metabolism
Chemical Substances	Antineoplastic Agents ; CD44 protein, human ; Cadherins ; Carrier Proteins ; Hyaluronan Receptors ; Microfilament Proteins ; Multienzyme Complexes ; Transforming Growth Factor beta ; Vimentin ; WIPF2 protein, human ; methylene tetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase ; Methylenetetrahydrofolate Dehydrogenase (NADP) (EC 1.5.1.5) ; Receptor, EphB4 (EC 2.7.10.1) ; Aminohydrolases (EC 3.5.4.-)
Language	English
Publishing date	2013-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.756
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Article ; Online: The L1TD1 protein interactome reveals the importance of post-transcriptional regulation in human pluripotency.

Emani, Maheswara Reddy / Närvä, Elisa / Stubb, Aki / Chakroborty, Deepankar / Viitala, Miro / Rokka, Anne / Rahkonen, Nelly / Moulder, Robert / Denessiouk, Konstantin / Trokovic, Ras / Lund, Riikka / Elo, Laura L / Lahesmaa, Riitta

Stem cell reports

2015 Volume 4, Issue 3, Page(s) 519–528

Abstract: The RNA-binding protein L1TD1 is one of the most specific and abundant proteins in pluripotent stem cells and is essential for the maintenance of pluripotency in human cells. Here, we identify the protein interaction network of L1TD1 in human embryonic ... ...

Abstract	The RNA-binding protein L1TD1 is one of the most specific and abundant proteins in pluripotent stem cells and is essential for the maintenance of pluripotency in human cells. Here, we identify the protein interaction network of L1TD1 in human embryonic stem cells (hESCs) and provide insights into the interactome network constructed in human pluripotent cells. Our data reveal that L1TD1 has an important role in RNA splicing, translation, protein traffic, and degradation. L1TD1 interacts with multiple stem-cell-specific proteins, many of which are still uncharacterized in the context of development. Further, we show that L1TD1 is a part of the pluripotency interactome network of OCT4, SOX2, and NANOG, bridging nuclear and cytoplasmic regulation and highlighting the importance of RNA biology in pluripotency.
MeSH term(s)	Amino Acid Sequence ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Nucleus/metabolism ; Cell Self Renewal/drug effects ; Cell Self Renewal/genetics ; Cytoplasm/metabolism ; Gene Expression Regulation ; Humans ; Molecular Sequence Data ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/drug effects ; Pluripotent Stem Cells/metabolism ; Proteasome Inhibitors/pharmacology ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping ; Protein Interaction Maps ; Protein Transport ; Proteins/chemistry ; Proteins/metabolism ; RNA Processing, Post-Transcriptional ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism
Chemical Substances	Carrier Proteins ; L1TD1 protein, human ; Proteasome Inhibitors ; Proteins ; RNA-Binding Proteins
Language	English
Publishing date	2015-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2015.01.014
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Article ; Online: Continuous hypoxic culturing of human embryonic stem cells enhances SSEA-3 and MYC levels.

Närvä, Elisa / Pursiheimo, Juha-Pekka / Laiho, Asta / Rahkonen, Nelly / Emani, Maheswara Reddy / Viitala, Miro / Laurila, Kirsti / Sahla, Roosa / Lund, Riikka / Lähdesmäki, Harri / Jaakkola, Panu / Lahesmaa, Riitta

PloS one

2013 Volume 8, Issue 11, Page(s) e78847

Abstract: Low oxygen tension (hypoxia) contributes critically to pluripotency of human embryonic stem cells (hESCs) by preventing spontaneous differentiation and supporting self-renewal. However, it is not well understood how hESCs respond to reduced oxygen ... ...

Abstract	Low oxygen tension (hypoxia) contributes critically to pluripotency of human embryonic stem cells (hESCs) by preventing spontaneous differentiation and supporting self-renewal. However, it is not well understood how hESCs respond to reduced oxygen availability and what are the molecular mechanisms maintaining pluripotency in these conditions. In this study we characterized the transcriptional and molecular responses of three hESC lines (H9, HS401 and HS360) on short (2 hours), intermediate (24 hours) and prolonged (7 days) exposure to low oxygen conditions (4% O2). In response to prolonged hypoxia the expression of pluripotency surface marker SSEA-3 was increased. Furthermore, the genome wide gene-expression analysis revealed that a substantial proportion (12%) of all hypoxia-regulated genes in hESCs, were directly linked to the mechanisms controlling pluripotency or differentiation. Moreover, transcription of MYC oncogene was induced in response to continuous hypoxia. At the protein level MYC was stabilized through phosphorylation already in response to a short hypoxic exposure. Total MYC protein levels remained elevated throughout all the time points studied. Further, MYC protein expression in hypoxia was affected by silencing HIF2α, but not HIF1α. Since MYC has a crucial role in regulating pluripotency we propose that induction of sustained MYC expression in hypoxia contributes to activation of transcriptional programs critical for hESC self-renewal and maintenance of enhanced pluripotent state.
MeSH term(s)	Antigens, Tumor-Associated, Carbohydrate/genetics ; Antigens, Tumor-Associated, Carbohydrate/metabolism ; Cell Differentiation ; Cell Hypoxia ; Cell Proliferation ; Cells, Cultured ; Embryonic Stem Cells/physiology ; Gene Expression Regulation ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Nanog Homeobox Protein ; Octamer Transcription Factor-3/genetics ; Octamer Transcription Factor-3/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; SOXB1 Transcription Factors/genetics ; SOXB1 Transcription Factors/metabolism ; Stage-Specific Embryonic Antigens/genetics ; Stage-Specific Embryonic Antigens/metabolism ; Transcriptional Activation ; Transcriptome
Chemical Substances	Antigens, Tumor-Associated, Carbohydrate ; Homeodomain Proteins ; MYC protein, human ; NANOG protein, human ; Nanog Homeobox Protein ; Octamer Transcription Factor-3 ; POU5F1 protein, human ; Proto-Oncogene Proteins c-myc ; SOX2 protein, human ; SOXB1 Transcription Factors ; Stage-Specific Embryonic Antigens ; stage-specific embryonic antigen-3
Language	English
Publishing date	2013-11-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0078847
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Article ; Online: A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases.

Gustafsson, Mika / Gawel, Danuta R / Alfredsson, Lars / Baranzini, Sergio / Björkander, Janne / Blomgran, Robert / Hellberg, Sandra / Eklund, Daniel / Ernerudh, Jan / Kockum, Ingrid / Konstantinell, Aelita / Lahesmaa, Riita / Lentini, Antonio / Liljenström, H Robert I / Mattson, Lina / Matussek, Andreas / Mellergård, Johan / Mendez, Melissa / Olsson, Tomas /

Pujana, Miguel A / Rasool, Omid / Serra-Musach, Jordi / Stenmarker, Margaretha / Tripathi, Subhash / Viitala, Miro / Wang, Hui / Zhang, Huan / Nestor, Colm E / Benson, Mikael

Science translational medicine

2015 Volume 7, Issue 313, Page(s) 313ra178

Abstract: Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are ... ...

Abstract	Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; GATA3 Transcription Factor/genetics ; Gene Regulatory Networks ; Genome-Wide Association Study ; Humans ; Multiple Sclerosis/diagnosis ; Multiple Sclerosis/genetics ; Multiple Sclerosis/immunology ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-maf/genetics ; Proto-Oncogene Proteins c-myb/genetics ; Rhinitis, Allergic, Seasonal/diagnosis ; Rhinitis, Allergic, Seasonal/genetics ; Rhinitis, Allergic, Seasonal/immunology ; Transcriptome
Chemical Substances	GATA3 Transcription Factor ; GATA3 protein, human ; MAF protein, human ; Proto-Oncogene Proteins c-maf ; Proto-Oncogene Proteins c-myb
Language	English
Publishing date	2015-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aad2722
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