• Intracranial aneurysm
• KLF6
• hypoxia
• immune microenvironment
• melatonin

• Humans
• Kruppel-Like Factor 6/genetics
• Kruppel-Like Factor 6/metabolism
• Melatonin
• Intracranial Aneurysm/genetics
• Intracranial Aneurysm/metabolism
• Intracranial Aneurysm/drug therapy
• Endothelin-1/metabolism
• Endothelin-1/genetics
• Male
• Muscle, Smooth, Vascular/metabolism
• Female

• Cardiac fibroblast
• Cardiac fibrosis
• Heart failure
• Transcription factor
• Transcriptional regulation

• Animals
• Kruppel-Like Factor 6/metabolism
• Kruppel-Like Factor 6/genetics
• Fibrosis/metabolism
• Mice
• Humans
• Male
• Mice, Inbred C57BL
• Fibroblasts/metabolism
• Myofibroblasts/metabolism
• Myofibroblasts/pathology
• Angiotensin II/pharmacology
• Myocardium/metabolism
• Myocardium/pathology
• Transforming Growth Factor beta/metabolism
• NF-kappa B/metabolism
• Cells, Cultured
• Kruppel-Like Transcription Factors/metabolism
• Kruppel-Like Transcription Factors/genetics
• Heart Failure/metabolism
• Heart Failure/pathology
• Heart Failure/genetics

• Alzheimer’s disease
• Bioinformatics
• Gender differences
• Meta-analysis
• Network analysis
• Pathway analysis
• Sex differences
• Single-cell transcriptomics
• Tg2576

• Mice
• Animals
• Alzheimer Disease/pathology
• Gene Regulatory Networks
• Gene Expression Profiling
• Brain/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism

• Kruppel-like factor 6 (KLF6)
• Specificity protein 1 (Sp1)
• collagen
• prolidase
• transcriptional regulation
• transforming growth factor beta (TGF-β)

• Animals
• Humans
• Mice
• Collagen/metabolism
• Dipeptidases
• Kruppel-Like Factor 6/genetics
• Sp1 Transcription Factor/genetics
• Sp1 Transcription Factor/metabolism
• Transcription Factors/metabolism
• Transforming Growth Factor beta/metabolism
• Transforming Growth Factor beta1/genetics
• Transforming Growth Factor beta1/metabolism
• Signal Transduction

• R01 AI136740 NIAID NIH HHS
• R56 AI122960 NIAID NIH HHS
• R01 DA057204 NIDA NIH HHS
• R25 GM059994 NIGMS NIH HHS
• R25 AI164610 NIAID NIH HHS
• R03 DA037779 NIDA NIH HHS
• R01 AI170228 NIAID NIH HHS
• U54 MD007586 NIMHD NIH HHS
• P30 AI110527 NIAID NIH HHS
• U54 MD007593 NIMHD NIH HHS

• Cell invasion
• RNA-protein interaction
• Signal transduction
• Transforming growth factor (TGFβ)
• lncRNA

• Humans
• Transforming Growth Factor beta/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Signal Transduction
• Smad Proteins/metabolism
• Neoplasm Invasiveness
• Cell Line, Tumor

• Bodossaki Foundation
• Alexander S. Onassis Public Benefit Foundation
• Ludwig Institute for Cancer Research
• Vetenskapsrådet
• European Research Council
• O.E. och Elda Johanssons stiftelse
• Petrus och Augusta Hedlunds Stiftelse
• Svenska Läkaresällskapet
• Magnus Bergvalls Stiftelse
• Cancerfonden
• Vetenskpasrådet
• Uppsala University

• Humans
• Alternative Splicing
• RNA Splicing/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Protein Isoforms/genetics
• Carcinogenesis
• Cell Transformation, Neoplastic

• P30 CA034196 NCI NIH HHS
• R01 HL151651 NHLBI NIH HHS
• R01 CA251138 NCI NIH HHS
• R01 GM138541 NIGMS NIH HHS
• R01 HL128239 NHLBI NIH HHS
• R01 CA248317 NCI NIH HHS

• Aging
• Boolean modelling
• Gene regulatory network Inference
• Hematopoietic stem cells
• Single-cell RNA seq

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, whose canonical pathway mainly regulates the genes involved in xenobiotic metabolism. However, it can also regulate several responses in a non-canonical manner, such as proliferation, differentiation, cell death and cell adhesion. AhR plays an important role in central nervous system tumors, as it can regulate several cellular responses via different pathways. The polymorphisms of the AHR gene have been associated with the development of gliomas. In addition, the metabolism of tumor cells promotes tumor growth, particularly in tryptophan synthesis, where some metabolites, such as kynurenine, can activate the AhR pathway, triggering cell proliferation in astrocytomas, medulloblastomas and glioblastomas. Furthermore, as part of the changes in neuroblastomas, AHR is able to downregulate the expression of proto-oncogene c-Myc, induce differentiation in tumor cells, and cause cell cycle arrest and apoptosis. Collectively, these data suggested that the modulation of the AhR pathway may downregulate tumor growth, providing a novel strategy for applications for the treatment of certain tumors through the control of the AhR pathway.

• aryl hydrocarbon receptor
• astrocytoma
• brain tumors
• medulloblastoma
• neuroblastoma

• Aging
• Cell cycle
• Differentiation
• Hematopoietic stem cell
• Single-cell RNA-seq
• Trajectories

• Aging
• Animals
• Cell Cycle
• Cell Differentiation
• Hematopoietic Stem Cells/physiology
• Male
• Mice
• RNA-Seq
• Single-Cell Analysis

• 20141PLBIO06 INCA
• #20161204989 Associacion pour la recherche contre le cancer
• 2017-00076284 Fondation de france
• AiMIDEX
• ITMO Cancer

Transforming growth factor-β1 (TGF-β1) is a pleiotropic factor sensed by most cells. It regulates a broad spectrum of cellular responses including hematopoiesis. In order to process TGF-β1-responses in time and space in an appropriate manner, there is a tight regulation of its signaling at diverse steps. The downstream signaling is mediated by type I and type II receptors and modulated by the ‘accessory’ receptor Endoglin also termed cluster of differentiation 105 (CD105). Endoglin was initially identified on pre-B leukemia cells but has received most attention due to its high expression on activated endothelial cells. In turn, Endoglin has been figured out as the causative factor for diseases associated with vascular dysfunction like hereditary hemorrhagic telangiectasia-1 (HHT-1), pre-eclampsia, and intrauterine growth restriction (IUPR). Because HHT patients often show signs of inflammation at vascular lesions, and loss of Endoglin in the myeloid lineage leads to spontaneous inflammation, it is speculated that Endoglin impacts inflammatory processes. In line, Endoglin is expressed on progenitor/precursor cells during hematopoiesis as well as on mature, differentiated cells of the innate and adaptive immune system. However, so far only pro-monocytes and macrophages have been in the focus of research, although Endoglin has been identified in many other immune system cell subsets. These findings imply a functional role of Endoglin in the maturation and function of immune cells. Aside the functional relevance of Endoglin in endothelial cells, CD105 is differentially expressed during hematopoiesis, arguing for a role of this receptor in the development of individual cell lineages. In addition, Endoglin expression is present on mature immune cells of the innate (i.e., macrophages and mast cells) and the adaptive (i.e., T-cells) immune system, further suggesting Endoglin as a factor that shapes immune responses. In this review, we summarize current knowledge on Endoglin expression and function in hematopoietic precursors and mature hematopoietic cells of different lineages.

• CD105
• Endoglin
• TGF-β-signaling
• adaptive immunity
• hematopoiesis
• hematopoietic stem cells
• innate immunity

• eigengene
• epithelial to mesenchymal transition
• meta-analysis
• module
• protein-protein interaction
• singular value decomposition
• weighted gene co-expression network analysis

Krüppel-like factor 6 (KLF6) is a transcription factor involved in the regulation of several cellular processes. Regarding its role in tumorigenesis, KLF6 is considered a tumor suppressor. Numerous reports demonstrate its frequent genomic loss or down-regulation, implying a functional inactivation in a broad range of human cancers. Previous work from our laboratory showed that the down-regulation of KLF6 expression in normal fibroblasts leads to cellular transformation, while its ectopic expression interferes with the oncogenic transformation triggered by activated Ras through a cell cycle arrest. We hypothesize that the growth suppressor activity of KLF6 may involve the induction of cellular senescence thereby helping to prevent the proliferation of cells at risk of neoplastic transformation. Here, we explored the association of KLF6 up-regulation in two different cellular senescence scenarios. We found that KLF6 silencing bypasses both oxidative and oncogene-induced senescence. In this context, KLF6 expression per se was capable to trigger cellular senescence in both normal and tumoral contexts. As such, the findings presented in this report provide insights into a potential mechanism by which KLF6 may play a suppressing role of uncontrolled or damaged cell proliferation.

• DNA damage
• KLF6
• cell proliferation
• cellular senescence
• ras oncogene

• Activin receptor-like kinase 1 (ALK1)
• Arteriovenous malformation
• Endoglin
• Epistaxis
• HHT
• Hereditary hemorrhagic telangiectasia

Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular disease derived from chronic liver disease, and its key pathogenesis is angiogenesis. Krüppel-like factor 6 (KLF6) mediates physiological repair and remodeling during vascular injury. However, the role of KLF6 in pulmonary microvascular endothelial cells (PMVECs) during angiogenesis of HPS and its underlying mechanism in HPS have not been investigated. Common bile duct ligation (CBDL) in rats can replicate pulmonary vascular abnormalities of human HPS. Here, we found that advanced pulmonary angiogenesis and pulmonary injury score coincided with the increase of KLF6 level in PMVECs of CBDL rat; KLF6 in PMVECs was also induced while cultured with CBDL rat serum in vitro. Inhibition of KLF6 dramatically suppressed PMVEC-mediated proliferation, migration and tube formation in vivo; this may be related to the downregulation of activin receptor-like kinase-1 (ALK1) and endoglin (ENG), which are transacted by KLF6. Bone morphogenetic protein 9 (BMP9) enhanced the expression of KLF6 in PMVECs and was involved in the angiogenesis of HPS. These results suggest that KLF6 triggers PMVEC-mediated angiogenesis of HPS and is aggravated by BMP9, and the inhibition of the BMP9/KLF6 axis may be an effective strategy for HPS treatment.

Summary: Krüppel-like factor 6, which is triggered by pulmonary injury and promoted by bone morphogenetic protein 9, mediates pulmonary angiogenesis in rat experimental hepatopulmonary syndrome and then aggravates lung dysfunction.

• Angiogenesis
• BMP9
• Hepatopulmonary syndrome (HPS)
• KLF6

Single-cell transcriptomic profiling is a powerful tool to explore cellular heterogeneity. However, most of these methods focus on the 3′-end of polyadenylated transcripts and provide only a partial view of the transcriptome. We introduce C1 CAGE, a method for the detection of transcript 5′-ends with an original sample multiplexing strategy in the C1^TM microfluidic system. We first quantifiy the performance of C1 CAGE and find it as accurate and sensitive as other methods in the C1 system. We then use it to profile promoter and enhancer activities in the cellular response to TGF-β of lung cancer cells and discover subpopulations of cells differing in their response. We also describe enhancer RNA dynamics revealing transcriptional bursts in subsets of cells with transcripts arising from either strand in a mutually exclusive manner, validated using single molecule fluorescence in situ hybridization.

Single-cell transcriptomic profiling allows the exploration of cellular heterogeneity but commonly focuses on the 3′-end of the transcript. Here the authors introduce C1 CAGE, which detects the 5′ transcript end in a multiplexed microfluidic system.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors (TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.

• Alternative isoforms
• Transcription factors
• Hepatocellular carcinoma
• Alternative splicing
• Hepatic differentiation
• Personalized treatment

• association
• gene expression
• quantitative traits
• transcription
• yak population

• atherosclerosis
• drug development
• endothelial cells
• inflammation
• shear stress
• vascular injury
• vascular smooth muscle cells

• RNA binding proteins
• RNA biology
• RNA-based therapies
• alternative splicing
• antisense oligonucleotides
• cancer
• isoforms
• oncogenes
• spliceosome
• splicing factors
• tumor suppressors

• Alternative Splicing/drug effects
• Alternative Splicing/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/pharmacology
• Spliceosomes/drug effects
• Spliceosomes/genetics
• Spliceosomes/metabolism

• R00 CA178206 NCI NIH HHS

• Antifibrotic therapy
• Chronic kidney disease
• Cytokines
• Inflammation
• Renal fibrosis

Platelets in the primary tumor microenvironment play crucial roles in regulating tumor growth, metastasis, and angiogenesis, but the underlying mechanisms are unclear. Here, we show that platelet releasates exhibited a proliferative effect on HeLa cells, and this effect correlated with a reduction of KLF6 expression. After incubation with either washed human platelets or collagen-related peptide (CRP) activated platelet releasates, expression of KLF6 in the HeLa cervical tumor cell line was markedly reduced. However, no significant difference was observed between control HeLa cells and HeLa cells incubated with resuspended activated platelet pellet. Moreover, the platelets’ promoting effect on HeLa cell growth was significantly abolished in KLF6 silenced HeLa cells. In addition, blocking TGF-β signaling with SB431542, a TGF-β receptor inhibitor, also counteracted the effect of platelets on proliferation and KLF6 expression in HeLa cells. From these findings, we conclude that platelet derived TGF-β promotes proliferation of HeLa cells by decreasing the expression of KLF6. The discovery that KLF6 is a key target of platelet-derived TGF-β signaling in HeLa cells identifies a potential new therapeutic target for the prevention and treatment of cervical carcinoma.

• HeLa cervical carcinoma cells
• Krüppel-like factor 6
• platelet
• platelet releasate
• transforming growth factor beta

• Bioinformatics
• Differentiation
• Gene arrays
• Inflammation
• Metabolism

• Animals
• Cells, Cultured
• Gene Regulatory Networks
• Genome-Wide Association Study
• Hepatocytes/immunology
• Hepatocytes/metabolism
• Humans
• Liver Diseases/etiology
• Liver Diseases/genetics
• Liver Diseases/immunology
• Liver Diseases/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Primary Cell Culture
• Species Specificity
• Transcriptome

• Seventh Framework Programme
• Bundesministerium für Bildung und Forschung

• T32 ES007254 NIEHS NIH HHS
• P30 ES006676 NIEHS NIH HHS
• F31 ES023305 NIEHS NIH HHS
• R01 ES026874 NIEHS NIH HHS
• R21 ES024607 NIEHS NIH HHS

Liver fibrosis is characterized by the excessive formation and accumulation of matrix proteins as a result of wound healing in the liver. A main event during fibrogenesis is the activation of the liver resident quiescent hepatic stellate cell (qHSC). Recent studies suggest that reversion of the activated HSC (aHSC) phenotype into a quiescent-like phenotype could be a major cellular mechanism underlying fibrosis regression in the liver, thereby offering new therapeutic perspectives for the treatment of liver fibrosis. Whether human HSCs have the ability to undergo a similar reversion in phenotype is currently unknown. The aim of the present study is to identify experimental conditions that can revert the in vitro activated phenotype of primary human HSCs and consequently to map the molecular events associated with this reversion process by gene expression profiling.

We find that epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) synergistically downregulate the expression of ACTA2 and LOX in primary human aHSCs. Their combination with oleic acid, palmitic acid, and retinol further potentiates a more quiescent-like phenotype as demonstrated by the abundant presence of retinyl ester-positive intra-cytoplasmic lipid droplets, low expression levels of activation markers, and a reduced basal as well as cytokine-stimulated proliferation and matrix metalloproteinase activity. Gene expression profiling experiments reveal that these in vitro reverted primary human HSCs (rHSCs) display an intermediary phenotype that is distinct from qHSCs and aHSCs. Interestingly, this intermediary phenotype is characterized by the increased expression of several previously identified signature genes of in vivo inactivated mouse HSCs such as CXCL1, CXCL2, and CTSS, suggesting also a potential role for these genes in promoting a quiescent-like phenotype in human HSCs.

We provide evidence for the ability of human primary aHSCs to revert in vitro to a transitional state through synergistic action of EGF, FGF2, dietary fatty acids and retinol, and provide a first phenotypic and genomic characterization of human in vitro rHSCs.

The online version of this article (doi:10.1186/s13069-015-0031-z) contains supplementary material, which is available to authorized users.

• Fibrosis
• Gene expression profiling
• Hepatic stellate cells
• Inactivation
• Quiescent
• Reversion

• liver fibrosis
• noncoding rnas (ncrnas)
• micrornas (mirnas)
• long noncoding rnas (lncrnas)

• Biomarkers/metabolism
• Humans
• Liver Cirrhosis/genetics
• Liver Cirrhosis/therapy
• MicroRNAs/physiology
• RNA, Untranslated/physiology

• R01 CA086978 NCI NIH HHS
• R01 CA193244 NCI NIH HHS
• R01CA086978 NCI NIH HHS
• R01CA193244 NCI NIH HHS

• Atherosclerosis
• Gene co-expression
• Microarray
• Transcriptome
• Transforming growth factor-beta 1
• Vascular smooth muscle cells

• Binding Sites
• Carotid Arteries/pathology
• Carotid Artery Diseases/metabolism
• Cells, Cultured
• Computer Simulation
• Early Growth Response Protein 1/physiology
• Gene Expression
• Gene Expression Regulation
• Humans
• Kruppel-Like Factor 6
• Kruppel-Like Transcription Factors/physiology
• Models, Genetic
• Multigene Family
• Muscle, Smooth, Vascular/pathology
• Myocytes, Smooth Muscle/metabolism
• Organ Specificity
• Promoter Regions, Genetic
• Proto-Oncogene Proteins/physiology
• Sp1 Transcription Factor/physiology
• Transforming Growth Factor beta1/genetics
• Transforming Growth Factor beta1/metabolism

Krüppel-like factor 11 (KLF11) and the highly homologous KLF10 proteins are transcription factors originating from duplication of the Drosophila melanogaster ancestor cabut. The function of these proteins in epithelial cells has been previously characterized. In the current study, we report a functional role for KLF11 in mesenchymal cells and in mesenchymal cell dysfunction, namely, fibrosis, and subsequently perform a detailed cellular, molecular, and in vivo characterization of this phenomenon. We find that, in cultured mesenchymal cells, enhanced expression of KLF11 results in activated extracellular matrix pathways, including collagen gene silencing and matrix metalloproteinases activation without changes in tissue inhibitors of metalloproteinases. Combined, reporter and chromatin immunoprecipitation assays demonstrate that KLF11 interacts directly with the collagen 1a2 (COL1A2) promoter in mesenchymal cells to repress its activity. Mechanistically, KLF11 regulates collagen gene expression through the heterochromatin protein 1 gene-silencing pathway as mutants defective for coupling to this epigenetic modifier lose the ability to repress COL1A2. Expression studies reveal decreased levels of KLF11 during liver fibrogenesis after chemically induced injury in vivo. Congruently, KLF11^-/- mice, which should be deficient in the hypothesized anti-fibrogenic brake imposed by this transcription factor, display an enhanced response to liver injury with increased collagen fibril deposition. Thus, KLFs expands the repertoire of transcription factors involved in the regulation of extracellular matrix proteins in mesenchymal cells and define a novel pathway that modulates the fibrogenic response during liver injury.

Krüppel-like factor 6 (KLF6) has been recently identified as a MEF2D target gene involved in neuronal cell survival. In addition, KLF6 and TGFβ have been shown to regulate each other’s expression in non-myogenic cell types. Since MEF2D and TGFβ also fulfill crucial roles in skeletal myogenesis, we wanted to identify whether KLF6 functions in a myogenic context.

KLF6 protein expression levels and promoter activity were analyzed using standard cellular and molecular techniques in cell culture.

We found that KLF6 and MEF2D are co-localized in the nuclei of mononucleated but not multinucleated myogenic cells and, that the MEF2 cis element is a key component of the KLF6 promoter region. In addition, TGFβ potently enhanced KLF6 protein levels and this effect was repressed by pharmacological inhibition of Smad3. Interestingly, pharmacological inhibition of MEK/ERK (1/2) signaling resulted in re-activation of the differentiation program in myoblasts treated with TGFβ, which is ordinarily repressed by TGFβ treatment. Conversely, MEK/ERK (1/2) inhibition had no effect on TGFβ-induced KLF6 expression whereas Smad3 inhibition negated this effect, together supporting the existence of two separable arms of TGFβ signaling in myogenic cells. Loss of function analysis using siRNA-mediated KLF6 depletion resulted in enhanced myogenic differentiation whereas TGFβ stimulation of myoblast proliferation was reduced in KLF6 depleted cells.

Collectively these data implicate KLF6 in myoblast proliferation and survival in response to TGFβ with consequences for our understanding of muscle development and a variety of muscle pathologies.

Krüppel-like factor-6 (KLF6) is a widely expressed member of the Sp1/KLF family of transcriptional regulators involved in differentiation, cell cycle control and proliferation in several cell systems. Even though the highest expression level of KLF6 has been detected in human and mice placenta, its function in trophoblast physiology is still unknown.

Herein, we explored KLF6 expression and sub-cellular distribution in human trophoblast cells differentiating into the syncytial pathway, and its role in the regulation of genes associated with placental development and pregnancy maintenance. Confocal immunofluorescence microscopy demonstrated that KLF6 is expressed throughout human cytotrophoblast differentiation showing no evident modifications in its nuclear and cytoplasmic localization pattern. KLF6 transcript and protein peaked early during the syncytialization process as determined by qRT-PCR and western blot assays. Overexpression of KLF6 in trophoblast-derived JEG-3 cells showed a preferential nuclear signal correlating with enhanced expression of human β-chorionic gonadotropin (βhCG) and pregnancy-specific glycoprotein (PSG) genes. Moreover, KLF6 transactivated βhCG5, PSG5 and PSG3 gene promoters. Deletion of KLF6 Zn-finger DNA binding domain or mutation of the consensus KLF6 binding site abolished transactivation of the PSG5 promoter.

Results are consistent with KLF6 playing a role as transcriptional regulator of relevant genes for placental differentiation and physiology such as βhCG and PSG, in agreement with an early and transient increase of KLF6 expression during trophoblast syncytialization.