scholarly journals Downregulation of GATA-1 expression during phorbol myristate acetate- induced megakaryocytic differentiation of human erythroleukemia cells

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1214-1221 ◽  
Author(s):  
W Dai ◽  
MJ Jr Murphy
Keyword(s):  
Transcription Factor ◽  
Steady State ◽  
Phorbol Myristate Acetate ◽  
Mrna Level ◽  
Terminal Differentiation ◽  
Specific Gene ◽  
Glycophorin A ◽  
Myristate Acetate ◽  
Megakaryocytic Differentiation ◽  
Hel Cells

Phorbol myristate acetate (PMA) induces the expression of megakaryocyte and/or platelet proteins during terminal differentiation of human erythroleukemia (HEL) cells. However, it is not established whether megakaryocytic differentiation is accompanied by the downregulation of the major erythroid transcription factor GATA-1 and the concomitant loss of the erythrocytic phenotype. Studies of the molecular mechanism of PMA-induced differentiation in HEL cells showed that when HEL cells are treated with PMA, they dramatically decrease the expression of the erythroid-specific gene glycophorin A at the mRNA level but apparently not at the steady-state protein level. In addition, a gel mobility shift assay was used to demonstrate that GATA-1, a major erythroid transcription factor normally present at high levels in HEL cells is downregulated after treatment with PMA. In contrast, the DNA-binding activities of transcription factors AP-1 and SP-1 are upregulated by PMA treatment of HEL cells. Furthermore, Northern blot analysis shows that PMA also downregulates the steady-state level of GATA-1 mRNA in HEL cells. The coordinated negative regulation of glycophorin A mRNA and GATA-1 expression after PMA treatment suggests that downregulation of GATA-1 expression may be partially responsible for the loss of the erythroid phenotype during megakaryocytic differentiation. The reported data also suggest that GATA-1 activity may not be essential for obtaining megakaryocytic phenotype during terminal differentiation in HEL cells.

scholarly journals Downregulation of GATA-1 expression during phorbol myristate acetate- induced megakaryocytic differentiation of human erythroleukemia cells

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1214-1221 ◽  
Author(s):  
W Dai ◽  
MJ Jr Murphy
Keyword(s):  
Transcription Factor ◽  
Steady State ◽  
Phorbol Myristate Acetate ◽  
Mrna Level ◽  
Terminal Differentiation ◽  
Specific Gene ◽  
Glycophorin A ◽  
Myristate Acetate ◽  
Megakaryocytic Differentiation ◽  
Hel Cells

Abstract Phorbol myristate acetate (PMA) induces the expression of megakaryocyte and/or platelet proteins during terminal differentiation of human erythroleukemia (HEL) cells. However, it is not established whether megakaryocytic differentiation is accompanied by the downregulation of the major erythroid transcription factor GATA-1 and the concomitant loss of the erythrocytic phenotype. Studies of the molecular mechanism of PMA-induced differentiation in HEL cells showed that when HEL cells are treated with PMA, they dramatically decrease the expression of the erythroid-specific gene glycophorin A at the mRNA level but apparently not at the steady-state protein level. In addition, a gel mobility shift assay was used to demonstrate that GATA-1, a major erythroid transcription factor normally present at high levels in HEL cells is downregulated after treatment with PMA. In contrast, the DNA-binding activities of transcription factors AP-1 and SP-1 are upregulated by PMA treatment of HEL cells. Furthermore, Northern blot analysis shows that PMA also downregulates the steady-state level of GATA-1 mRNA in HEL cells. The coordinated negative regulation of glycophorin A mRNA and GATA-1 expression after PMA treatment suggests that downregulation of GATA-1 expression may be partially responsible for the loss of the erythroid phenotype during megakaryocytic differentiation. The reported data also suggest that GATA-1 activity may not be essential for obtaining megakaryocytic phenotype during terminal differentiation in HEL cells.

PMA Responsive Sequence (s) in Gαq Promoter during Megakaryocytic Differentiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4246-4246
Author(s):  
Gauthami S. Jalagadugula ◽  
Danny Dhanasekharan ◽  
A.Koneti Rao
Keyword(s):  
Transcription Factor ◽  
Protein Binding ◽  
Reporter Gene ◽  
Transcriptional Control ◽  
Nuclear Protein ◽  
Genomic Region ◽  
Luciferase Reporter ◽  
Upstream Region ◽  
Megakaryocytic Differentiation ◽  
Hel Cells

Abstract Human erthroleukemia cells (HEL) differentiate towards megakaryocytic (MK) phenotype when stimulated with phorbol 12-myristate-13-acetate (PMA). We observed that the expression of Gq, a protein that plays a major role in platelet signal transduction, is increased in PMA-treated HEL cells. Western blotting revealed that Gq is upregulated in PMA-treated cells relative to untreated cells. Gq gene induction by PMA treatment was investigated with respect to transcriptional control. Serial 5′-truncations of the upstream region (upto 2727 bp from the ATG) of Gq gene were fused to a luciferase (Luc) reporter gene vector, PGL-3 Basic, and were transiently transfected into HEL cells in the absence and presence of PMA (10 nM). After 24 h, reporter gene activities were measured using Dual Luciferase Reporter Assay System (Promega). A reporter plasmid −1042 bp-Luc with a genomic region −1042/−1 showed a 12 fold activity in PMA treated cells and 4 fold activity in untreated cells. Its truncated plasmid with the genomic region −1036/−1 showed a decrease in luciferase activity by 50% in treated cells; and the activity became identical to that in untreated cells. Further truncation between −1036 and −1011 caused a complete loss of activity in both the cells. Thus, a PMA responsive element was localized to a region between −1042 and −1037 bp. Transcription factor data base search (TFSEARCH) predicted two consensus sites for early growth response factor EGR-1 at -1042/−1031 and −1026/−1015. Gel shift studies were performed with two oligos, −1042/−1012 and −1036/−1012, and nuclear extracts from PMA- treated and untreated cells. The studies with −1042/−1012 probe and extracts from treated cells showed that there was nuclear protein binding, which was abolished by competition with the consensus EGR-1 sequence. In extracts from untreated cells, the protein binding was observed but was not competed with consensus EGR-1 sequence. This suggests EGR-1 binding to the region −1042/−1012 in PMA-treated cells and role for this transcription factor in inducing Gq promoter activity. Moreover, studies on the region −1036/−1012 showed nuclear protein binding that was identical between extracts of untreated and treated cells, and it was not competed with consensus EGR-1 sequence. These findings suggest that, EGR-1 binding is localized to −1042/−1037, but not to −1036/−1012. Conclusion: A PMA responsive sequence (−1042/−1037) was identified in the Gq promoter. Our studies suggest that EGR-1 binding to this sequence confers the PMA responsive activity. These studies provide further evidence that EGR-1 plays an important role in the upregulation of Gq expression during PMA induced megakaryocytic differentiation.

scholarly journals Inhibition of protein kinase C suppresses megakaryocytic differentiation and stimulates erythroid differentiation in HEL cells

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Y Hong ◽  
JF Martin ◽  
W Vainchenker ◽  
JD Erusalimsky
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Erythroid Differentiation ◽  
Inhibitory Effect ◽  
Glycophorin A ◽  
Maximal Effect ◽  
Megakaryocytic Differentiation ◽  
Kinase C ◽  
Hel Cells ◽  
Dose Dependent

The bisindolylmaleimide, GF109203X (2-[1-(3-dimethylaminopropyl)-1H- indol-3-yl]-3-(1H-indol-3-yl)-maleimide ), a highly selective inhibitor of protein kinase C (PKC), was used to test the role of this enzyme in phorbol ester-induced megakaryocytic differentiation of HEL cells. Treatment of these cells with 10 nmol/L phorbol 12-myristate 13-acetate (PMA) for 3 days caused a complete inhibition of proliferation and a threefold increase in the surface expression of glycoprotein (GP) IIIa, a marker of megakaryocytic differentiation that forms part of the fibrinogen receptor complex, GPIIb/IIIa. A similar effect was observed with phorbol 12,13-dibutyrate, but not with the biologically inactive derivative PMA-4-O-methyl ether. The PMA-induced increase in GPIIIa expression was completely inhibited by GF109203X in a dose-dependent manner (IC50 = 0.5 mumol/L), with a maximal effect at 2.5 to 5.0 mumol/L. GF109203X also blocked the inhibitory effect of PMA on cell growth and inhibited PMA-stimulated phosphorylation of the 47-kD PKC substrate, pleckstrin. Incubation of HEL cells with 25 mumol/L hemin for 3 days caused a fourfold to fivefold increase in expression of the erythroid differentiation marker, glycophorin A. In contrast to the inhibitory effect of GF109203X on GPIIIa expression, hemin induction of glycophorin A was enhanced by this compound. Furthermore, GF109203X alone caused a dose-dependent increase in glycophorin A expression, and induced hemoglobinization. Consistent with these changes, Northern blot analysis revealed that GF109203X treatment reduced the steady-state level of GPIIb mRNA and increased those for glycophorin A and gamma-globin. These results suggest that PKC may act as a developmental switch controlling erythroid/megakaryocytic differentiation.

scholarly journals Regulation of CDC6, Geminin, and CDT1 in Human Cells that Undergo Polyploidization

2002 ◽  
Vol 13 (11) ◽  
pp. 3989-4000 ◽  
Author(s):  
Rodrigo Bermejo ◽  
Nuria Vilaboa ◽  
Carmela Calés
Keyword(s):  
Cell Lines ◽  
Cyclin E ◽  
Terminal Differentiation ◽  
K562 Cells ◽  
Active Role ◽  
Key Factors ◽  
Rna Transcription ◽  
Megakaryocytic Differentiation ◽  
Hel Cells

Endomitosis is the process by which mammalian megakaryocytes become polyploid during terminal differentiation. As in other endoreplicating cells, cyclin-cdk complexes are distinctly regulated, probably to overcome the strict mechanisms that prevent rereplication in most somatic cells. We have asked whether key factors involved in the assembly and licensing of replication origins are equally regulated during endomitosis. Cdc6, cdt1, and geminin expression was analyzed during differentiation of two human megakaryoblastic cell lines, HEL and K562, which respectively do and do not establish endoreplication cycles. Geminin was downregulated, whereas cdt1 levels were maintained upon differentiation of both cell lines, independently of whether cells entered extra S-phases. In contrast, cdc6 was present and remained nuclear only in differentiated endoreplicating cells. Interestingly, cdc6 protein expression was reestablished in K562 cells that underwent endomitosis after transient or stable cyclin E overexpression. The high levels of cyclin E reached in these cells appeared to influence the stabilization of cdc6 protein rather than its RNA transcription rate. Finally, cdc6 overexpression drove HEL cells into endoreplication cycles in the absence of differentiation stimuli. Our results show that both cdt1 and cdc6 are differentially regulated during megakaryocytic differentiation and suggest an active role of cdc6 in endomitosis.

C/EBPβ-Mediated Expansion of Hematopoietic Stem/Progenitors Precedes ‘Emergency’ Granulopoiesis Induced by Candidemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2336-2336
Author(s):  
Akihiro Tamura ◽  
Hideyo Hirai ◽  
Yoshihiro Hayashi ◽  
Hisayuki Yao ◽  
Satoshi Yoshioka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Post Infection ◽  
Conflicts Of Interest ◽  
Mrna Level ◽  
Cathepsin G ◽  
Hematopoietic Stem ◽  
Myeloid Progenitors

Abstract Abstract 2336 Granulopoiesis, the process of granulocyte production in the bone marrow (BM), is tightly regulated to meet host demands during both 'steady state' and 'emergency' situations such as infections. The transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) plays critical roles in emergency granulopoiesis (Hirai et al. Nat Immunology, 2006). However, the precise developmental stages in which C/EBPβ is required are unknown. In this study, we investigated the roles of C/EBPβ in the proliferation and differentiation of prospectively identified intermediates between hematopoietic stem cells and mature granulocytes in mouse BM. In order to analyze the mouse BM cells undergoing granulopoiesis, novel flow cytometric method was developed. Mouse BM cells retaining the ability to give rise to granulocytes were dissected into five distinct subpopulations (#1–#5) according to their levels of c-kit and Ly-6G expression. Upon infection of Candida albicans (4 × 106 CFU/20 g body weight/mouse) on day 1, C/EBPβ was upregulated at the protein level but not at mRNA level in all the granulopoietic subpopulations, suggesting the importance of the transcription factor in □emergency' granulopoiesis. Then, the role of C/EBPβ was further assessed by analyzing C/EBPβ knockout (KO) mice. At steady state, the distribution of granulopoietic cells in BM of C/EBPβ KO mice at □esteady state' was identical to that of wild type (WT) mice. In contrast, the rapid increase in immature subpopulations #1 and #2 observed in WT mice at 1 day post-infection was significantly attenuated in C/EBPβ KO mice. The levels of mRNA expression for granule proteins (cathepsin G, myeloperoxidase, elastase 2, proteinase 3, lactoferrin and MMP9) within each subpopulation from WT and C/EBPβ KO mice were identical at both steady state and during infection. When the cell cycle status of these models was evaluated using in vivo BrdU labeling experiments, incorporation of BrdU in subpopulation #1 and #2 in C/EBPβ KO mice was always slightly lower than in WT mice, but the differences were not statistically significant. These findings suggest that C/EBPβ is required for efficient proliferation of early granulocytic precursors but not directly involved in the differentiation/maturation process. To elucidate the roles of C/EBPβ in the proliferation of the early granulopoietic subpopulations, the hematopoietic stem cells (HSCs) and myeloid progenitor compartments were analyzed in WT and C/EBPβ KO mice. The frequency and number of c-kit+ Sca-1+ lineage markers− HSC were identical between WT mice and C/EBPβ KO mice during the steady state, and were not significantly affected on day 1 post-infection. Induction of candidemia increased the frequency and number of granulocyte-macrophage progenitors (GMP) in WT mice, and these increases were significantly attenuated in C/EBPβ KO mice. Upon induction of candidemia, the frequency of BrdU-positive cells in the HSC and common myeloid progenitors (CMP) populations from WT mice increased significantly; however, an increase of BrdU-positive cells was observed only within the HSC compartment in C/EBPβ KO mice, and at a lower level than that in WT mice Taken together, these data suggest that the proliferation of early granulocytic precursors is tightly coupled to differentiation/maturation and that C/EBPβ is involved in the efficient amplification of early granulocyte precursors including HSC and myeloid progenitors during candidemia-induced 'emergency' granulopoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inhibition of protein kinase C suppresses megakaryocytic differentiation and stimulates erythroid differentiation in HEL cells

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 123-131 ◽  
Author(s):  
Y Hong ◽  
JF Martin ◽  
W Vainchenker ◽  
JD Erusalimsky
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Erythroid Differentiation ◽  
Inhibitory Effect ◽  
Glycophorin A ◽  
Maximal Effect ◽  
Megakaryocytic Differentiation ◽  
Kinase C ◽  
Hel Cells ◽  
Dose Dependent

Abstract The bisindolylmaleimide, GF109203X (2-[1-(3-dimethylaminopropyl)-1H- indol-3-yl]-3-(1H-indol-3-yl)-maleimide ), a highly selective inhibitor of protein kinase C (PKC), was used to test the role of this enzyme in phorbol ester-induced megakaryocytic differentiation of HEL cells. Treatment of these cells with 10 nmol/L phorbol 12-myristate 13-acetate (PMA) for 3 days caused a complete inhibition of proliferation and a threefold increase in the surface expression of glycoprotein (GP) IIIa, a marker of megakaryocytic differentiation that forms part of the fibrinogen receptor complex, GPIIb/IIIa. A similar effect was observed with phorbol 12,13-dibutyrate, but not with the biologically inactive derivative PMA-4-O-methyl ether. The PMA-induced increase in GPIIIa expression was completely inhibited by GF109203X in a dose-dependent manner (IC50 = 0.5 mumol/L), with a maximal effect at 2.5 to 5.0 mumol/L. GF109203X also blocked the inhibitory effect of PMA on cell growth and inhibited PMA-stimulated phosphorylation of the 47-kD PKC substrate, pleckstrin. Incubation of HEL cells with 25 mumol/L hemin for 3 days caused a fourfold to fivefold increase in expression of the erythroid differentiation marker, glycophorin A. In contrast to the inhibitory effect of GF109203X on GPIIIa expression, hemin induction of glycophorin A was enhanced by this compound. Furthermore, GF109203X alone caused a dose-dependent increase in glycophorin A expression, and induced hemoglobinization. Consistent with these changes, Northern blot analysis revealed that GF109203X treatment reduced the steady-state level of GPIIb mRNA and increased those for glycophorin A and gamma-globin. These results suggest that PKC may act as a developmental switch controlling erythroid/megakaryocytic differentiation.

Sevoflurane Inhibits Phorbol-Myristate-Acetate-induced Activator Protein-1 Activation in Human T Lymphocytes in Vitro : Potential Role of the p38-Stress Kinase Pathway

2004 ◽  
Vol 101 (3) ◽  
pp. 710-721 ◽  
Author(s):  
Torsten Loop ◽  
Patrick Scheiermann ◽  
David Doviakue ◽  
Frank Musshoff ◽  
Matjaz Humar ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Kinases ◽  
Phorbol Myristate Acetate ◽  
Volatile Anesthetics ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Myristate Acetate ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein

Background Modulation of immune defense mechanisms by volatile anesthetics during general anesthesia may compromise postoperative immune competence and healing reactions and affect the infection rate and the rate of tumor metastases disseminated during surgery. Several mechanisms have been suggested to account for these effects. The current study was undertaken to examine the molecular mechanisms underlying these observations. Methods Effects of sevoflurane, isoflurane, and desflurane were studied in vitro in primary human CD3 T-lymphocytes. DNA-binding activity of the transcription factor activator protein-1 (AP-1) was assessed using an electrophoretic mobility shift assay. Phorbol-myristate-acetate-dependent effects of sevoflurane on the phosphorylation of the mitogen-activated protein kinases were studied using Western blots, the trans-activating potency of AP-1 was determined using reporter gene assays, and the cytokine release was measured using enzyme-linked immunosorbent assays. Results Sevoflurane inhibited activation of the transcription factor AP-1. This effect was specific, as the activity of nuclear factor kappabeta, nuclear factor of activated T cells, and specific protein-1 was not altered and several other volatile anesthetics studied did not affect AP-1 activation. Sevoflurane-mediated suppression of AP-1 could be observed in primary CD3 lymphocytes from healthy volunteers, was time-dependent and concentration-dependent, and occurred at concentrations that are clinically achieved. It resulted in an inhibition of AP-1-driven reporter gene activity and of the expression of the AP-1 target gene interleukin-3. Suppression of AP-1 was associated with altered phosphorylation of p38 mitogen-activated protein kinases. Conclusion The data demonstrate that sevoflurane is a specific inhibitor of AP-1 and may thus provide a molecular mechanism for the antiinflammatory effects associated with sevoflurane administration.

scholarly journals Multi-resolution network modelling of T-cells for precision medicine of multiple sclerosis

2017 ◽  
Author(s):  
Mika Gustafsson
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Transcription Factor ◽  
Mrna Level ◽  
Complex Diseases ◽  
Patient Specific ◽  
Specific Gene ◽  
Disease Genes ◽  
Multiple Time ◽  
Time Points

Background: Due to the interplay between many factors, systems medicine of complex diseases is most often centered either on individual genes, or on statistical associations. Complex network analysis could potentially explain systems-wide differences between patients and controls. In order to achieve this understanding using incomplete existing data, we need these powerful coarse-graining procedures. First, disease genes have been shown to co-localise for many complex diseases in protein-interaction networks, and thereby forming disease modules, however the identification of such modules is not well-defined (Gustafsson Genome Medicine 2014). We have developed ModifieR, an R-package which combines 10 existing and new methods using statistical overlaps between multiple omics as a guiding principle. Second, upstream hub transcription factors (TFs) regulating those modules have shown to be good candidates for early predictive medicine (Gustafsson Science Transl Med 2015). Third, those TFs tend to be interconnected and form core circuits, which have a great genome-wide impact, and could be modelled by our recent dynamic ordinary differential equation based modelling tool, LASSIM (Magnusson, PLoS Comput Biol 2017, https://gitlab.com/Gustafsson-lab/ ). Each of these concepts could synergistically increase the analysis resolution. A critical problem is that parts of the models are patient-specific while parts are highly conserved across patients, which we work to resolve. Methods: A key feature to estimate patient specific disease-relevant networks is multiple time-points omics in cells reflecting different disease-relevant stages. We hypothesise that by connecting patients at multiple stages we can infer the disease-relevant patient specific gene regulatory networks, from which we can draw statistical conclusions (extension of the work in Hellberg Cell Reports 2016). For this purpose, we are performing modelling of CD4+ T-cells in multiple sclerosis using generally applicable principles in open access pipelines. Briefly, we apply a linear transcription factor-target model based on eQTL-targeted sequencing and patients in two time-points. The model uses L1 constraints, similar to our previous models (Gustafsson Science Transl Medicine 2015, Gustafsson IEEE 2005), but is allowed to infer transcription factor activity based on target gene expression, using the CVX optimisation toolbox. Results: We found that the inferred patient specific GRN models with L1 constraint predicted 50% of the transcriptomic changes using cross-validation. Generally, we found that the TF activity poorly correlated with its mRNA level. Moreover, we found TFs with a significantly higher effect in patients than controls. Discussion: My research focus on three recent network medicine concepts that enable a gradually increased resolution of modelling for complex diseases, which I ultimately aim at integrating in a unifying precisions medicine toolbox.

scholarly journals Multi-resolution network modelling of T-cells for precision medicine of multiple sclerosis

2017 ◽  
Author(s):  
Mika Gustafsson
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Transcription Factor ◽  
Mrna Level ◽  
Complex Diseases ◽  
Patient Specific ◽  
Specific Gene ◽  
Disease Genes ◽  
Multiple Time ◽  
Time Points

Background: Due to the interplay between many factors, systems medicine of complex diseases is most often centered either on individual genes, or on statistical associations. Complex network analysis could potentially explain systems-wide differences between patients and controls. In order to achieve this understanding using incomplete existing data, we need these powerful coarse-graining procedures. First, disease genes have been shown to co-localise for many complex diseases in protein-interaction networks, and thereby forming disease modules, however the identification of such modules is not well-defined (Gustafsson Genome Medicine 2014). We have developed ModifieR, an R-package which combines 10 existing and new methods using statistical overlaps between multiple omics as a guiding principle. Second, upstream hub transcription factors (TFs) regulating those modules have shown to be good candidates for early predictive medicine (Gustafsson Science Transl Med 2015). Third, those TFs tend to be interconnected and form core circuits, which have a great genome-wide impact, and could be modelled by our recent dynamic ordinary differential equation based modelling tool, LASSIM (Magnusson, PLoS Comput Biol 2017, https://gitlab.com/Gustafsson-lab/ ). Each of these concepts could synergistically increase the analysis resolution. A critical problem is that parts of the models are patient-specific while parts are highly conserved across patients, which we work to resolve. Methods: A key feature to estimate patient specific disease-relevant networks is multiple time-points omics in cells reflecting different disease-relevant stages. We hypothesise that by connecting patients at multiple stages we can infer the disease-relevant patient specific gene regulatory networks, from which we can draw statistical conclusions (extension of the work in Hellberg Cell Reports 2016). For this purpose, we are performing modelling of CD4+ T-cells in multiple sclerosis using generally applicable principles in open access pipelines. Briefly, we apply a linear transcription factor-target model based on eQTL-targeted sequencing and patients in two time-points. The model uses L1 constraints, similar to our previous models (Gustafsson Science Transl Medicine 2015, Gustafsson IEEE 2005), but is allowed to infer transcription factor activity based on target gene expression, using the CVX optimisation toolbox. Results: We found that the inferred patient specific GRN models with L1 constraint predicted 50% of the transcriptomic changes using cross-validation. Generally, we found that the TF activity poorly correlated with its mRNA level. Moreover, we found TFs with a significantly higher effect in patients than controls. Discussion: My research focus on three recent network medicine concepts that enable a gradually increased resolution of modelling for complex diseases, which I ultimately aim at integrating in a unifying precisions medicine toolbox.

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