KLF4 induces Mesenchymal-Epithelial Transition (MET) by suppressing multiple EMT-inducing transcription factors

Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs) - TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, FOXC2 - are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2, GRHL1/2). Here, using mechanism-based mathematical modeling, we show that the transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote phenotypic shift toward a more epithelial state, an observation suggested by negative correlation of KLF4 with EMT-TFs and with transcriptomic based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at an epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.

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KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors

Cancers ◽

10.3390/cancers13205135 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5135

Author(s):

Ayalur Raghu Subbalakshmi ◽

Sarthak Sahoo ◽

Isabelle McMullen ◽

Aaditya Narayan Saxena ◽

Sudhanva Kalasapura Venugopal ◽

...

Keyword(s):

Transcription Factors ◽

Patient Survival ◽

Dynamic Processes ◽

State Transitions ◽

Specific Manner ◽

Context Specific ◽

Phenotypic Shift ◽

Acting In Concert ◽

Epithelial State ◽

Mesenchymal Epithelial Transition

Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2—are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.

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SOX transcription factors direct TCF-independent WNT/beta-catenin transcription.

10.1101/2021.08.25.457694 ◽

2021 ◽

Author(s):

Shreyasi Mukherjee ◽

David M Luedeke ◽

Leslie Brown ◽

Aaron Zorn

Keyword(s):

Transcription Factors ◽

Tissue Regeneration ◽

Pluripotent Stem Cells ◽

Target Genes ◽

Fundamental Question ◽

Beta Catenin ◽

Cell Type ◽

Time Resolved ◽

Specific Manner ◽

Context Specific

WNT/β-catenin signaling regulates gene expression across numerous biological contexts including development, stem cell homeostasis and tissue regeneration, and dysregulation of this pathway has been implicated in many diseases including cancer. One fundamental question is how distinct WNT target genes are activated in a context-specific manner, given the dogma that most, if not all, WNT/β-catenin responsive transcription is mediated by TCF/LEF transcription factors (TFs) that have similar DNA-binding specificities. Here we show that the SOX family of TFs direct lineage-specific WNT/β-catenin responsive transcription during the differentiation of human pluripotent stem cells (hPSCs) into definitive endoderm (DE) and neuromesodermal progenitors (NMPs). Using time-resolved multi-omics analyses, we show that β-catenin association with chromatin is highly dynamic, colocalizing with distinct TCFs and/or SOX TFs at distinct stages of differentiation, indicating both cooperative and competitive modes of genomic interactions. We demonstrate that SOX17 and SOX2 are required to recruit β-catenin to hundreds of lineage-specific WNT-responsive enhancers, many of which are not occupied by TCFs. At a subset of these TCF-independent enhancers, SOX TFs are required to both establish a permissive chromatin landscape and recruit a WNT-enhanceosome complex that includes β-catenin, BCL9, PYGO and transcriptional coactivators to direct SOX/β-catenin-dependent transcription. Given that SOX TFs are expressed in almost every cell type, these results have broad mechanistic implications for the specificity of WNT responses across many developmental and disease contexts.

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The histone variant H2A.Z and chromatin remodeler BRAHMA act coordinately and antagonistically to regulate transcription and nucleosome dynamics in Arabidopsis

10.1101/243790 ◽

2018 ◽

Author(s):

E. Shannon Torres ◽

Roger B. Deal

Keyword(s):

Transcriptional Regulation ◽

Transcription Factors ◽

Binding Sites ◽

Transcriptional Repression ◽

Nucleosome Positioning ◽

Chromatin Organization ◽

Histone H2a ◽

Nucleosome Dynamics ◽

Environmentally Responsive ◽

Context Specific

ABSTRACTPlants adapt to changes in their environment by regulating transcription and chromatin organization. The histone H2A variant H2A.Z and the SWI2/SNF2 ATPase BRAHMA have overlapping roles in positively and negatively regulating environmentally responsive genes in Arabidopsis, but the extent of this overlap was uncharacterized. Both have been associated with various changes in nucleosome positioning and stability in different contexts, but their specific roles in transcriptional regulation and chromatin organization need further characterization. We show that H2A.Z and BRM act both cooperatively and antagonistically to contribute directly to transcriptional repression and activation of genes involved in development and response to environmental stimuli. We identified 8 classes of genes that show distinct relationships between H2A.Z and BRM and their roles in transcription. We found that H2A.Z contributes to a range of different nucleosome properties, while BRM stabilizes nucleosomes where it binds and destabilizes and/or repositions flanking nucleosomes. H2A.Z and BRM contribute to +1 nucleosome destabilization, especially where they coordinately regulate transcription. We also found that at genes regulated by both BRM and H2A.Z, both factors overlap with the binding sites of light-regulated transcription factors PIF4, PIF5, and FRS9, and that some of the FRS9 binding sites are dependent on H2A.Z and BRM for accessibility. Collectively, we comprehensively characterized the antagonistic and cooperative contributions of H2A.Z and BRM to transcriptional regulation, and illuminated their interrelated roles in chromatin organization. The variability observed in their individual functions implies that both BRM and H2A.Z have more context-specific roles within diverse chromatin environments than previously assumed.

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STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

Nature Communications ◽

10.1038/s41467-020-18648-6 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Yongyao Fu ◽

Jocelyn Wang ◽

Gayathri Panangipalli ◽

Benjamin J. Ulrich ◽

Byunghee Koh ◽

...

Keyword(s):

Transcription Factors ◽

Cell Differentiation ◽

Tumor Immunity ◽

Th17 Cells ◽

Allergic Airway Inflammation ◽

T Helper Cell ◽

T Helper ◽

Th9 Cells ◽

Specific Manner ◽

Pioneer Factor

Abstract T helper cell differentiation requires lineage-defining transcription factors and factors that have shared expression among multiple subsets. BATF is required for development of multiple Th subsets but functions in a lineage-specific manner. BATF is required for IL-9 production in Th9 cells but in contrast to its function as a pioneer factor in Th17 cells, BATF is neither sufficient nor required for accessibility at the Il9 locus. Here we show that STAT5 is the earliest factor binding and remodeling the Il9 locus to allow BATF binding in both mouse and human Th9 cultures. The ability of STAT5 to mediate accessibility for BATF is observed in other Th lineages and allows acquisition of the IL-9-secreting phenotype. STAT5 and BATF convert Th17 cells into cells that mediate IL-9-dependent effects in allergic airway inflammation and anti-tumor immunity. Thus, BATF requires the STAT5 signal to mediate plasticity at the Il9 locus.

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miR-27 and miR-125 Distinctly Regulate Muscle-Enriched Transcription Factors in Cardiac and Skeletal Myocytes

BioMed Research International ◽

10.1155/2015/391306 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Estefania Lozano-Velasco ◽

Jennifer Galiano-Torres ◽

Alvaro Jodar-Garcia ◽

Amelia E. Aranega ◽

Diego Franco

Keyword(s):

Transcription Factors ◽

Cardiac Development ◽

Protein Translation ◽

Cell Type ◽

Atrial Cardiomyocytes ◽

Skeletal Myocytes ◽

Specific Manner ◽

A Cell ◽

Cell Type Specific

MicroRNAs are noncoding RNAs of approximately 22–24 nucleotides which are capable of interacting with the 3′ untranslated region of coding RNAs (mRNAs), leading to mRNA degradation and/or protein translation blockage. In recent years, differential microRNA expression in distinct cardiac development and disease contexts has been widely reported, yet the role of individual microRNAs in these settings remains largely unknown. We provide herein evidence of the role of miR-27 and miR-125 regulating distinct muscle-enriched transcription factors. Overexpression of miR-27 leads to impair expression ofMstnandMyocdin HL1 atrial cardiomyocytes but not in Sol8 skeletal muscle myoblasts, while overexpression of miR-125 resulted in selective upregulation ofMef2din HL1 atrial cardiomyocytes and downregulation in Sol8 cells. Taken together our data demonstrate that a single microRNA, that is, miR-27 or miR-125, can selectively upregulate and downregulate discrete number of target mRNAs in a cell-type specific manner.

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A proximal tissue-specific module and a distal negative regulatory module control apolipoprotein(a) gene transcription

Biochemical Journal ◽

10.1042/bj20030985 ◽

2004 ◽

Vol 379 (1) ◽

pp. 151-159 ◽

Cited By ~ 9

Author(s):

Sarita NEGI ◽

Saurabh K. SINGH ◽

Nirupma PATI ◽

Vikas HANDA ◽

Ruchi CHAUHAN ◽

...

Keyword(s):

Transcription Factors ◽

Gene Transcription ◽

Hela Cells ◽

Hepg2 Cells ◽

Regulatory Element ◽

Regulatory Elements ◽

Tissue Specific ◽

Apolipoprotein A ◽

Regulatory Module ◽

Specific Manner

The apo(a) [apolipoprotein(a)] gene is responsible for variations in plasma lipoprotein(a), high levels of which are a risk factor for atherosclerosis and myocardial infarction. The apo(a) promoter stimulates the expression of reporter genes in HepG2 cells, but not in HeLa cells. In the present study, we demonstrate that the 1.4 kb apo(a) promoter comprises two composite regulatory regions: a distal negative regulatory module (positions −1432 to −716) and a proximal tissue-specific module (−716 to −616). The distal negative regulatory module contains two strong negative regulatory regions [polymorphic PNR (pentanucleotide repeat region) and NREβ (negative regulatory element β)], which sandwich the postive regulatory region PREβ (positive regulatory element β). The PNR was shown to bind to transcription factors in a tissue-specific manner, whereas the ubiquitous transcription factors hepatocyte nuclear factor 3α and GATA binding protein 4 bound to NREβ to repress gene transcription. The proximal tissue-specific module contains two regulatory elements: an activating region (PREα) that activates transcription in HepG2 cells, and NREα, which is responsible for repressing the apo(a) gene in HeLa cells. NREα binds to a HeLa-specific repressor. These multiple regulatory elements might work co-operatively to finely regulate apo(a) gene expression. Although the tissue-specific module is required for apo(a) gene activation and repression in a tissue-specific manner, the combinatorial interplay of the distal and proximal regulators might define the complex pathway(s) of apo(a) gene regulation.

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Co-ordinate high level expression of the murine α- and β-globin genes is regulated in a context-specific manner by erythroid Krüppel-like factor (EKLF)

Blood Cells Molecules and Diseases ◽

10.1016/j.bcmd.2006.10.036 ◽

2007 ◽

Vol 38 (2) ◽

pp. 134 ◽

Cited By ~ 1

Author(s):

John M. Cunningham ◽

Valerie Jansen ◽

Shaji Ramachandran ◽

Aurelie Desgardin ◽

Jin He ◽

...

Keyword(s):

Globin Genes ◽

High Level Expression ◽

Specific Manner ◽

Context Specific ◽

High Level

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Lumican Exhibits Anti-Angiogenic Activity in a Context Specific Manner

Cancer Microenvironment ◽

10.1007/s12307-013-0134-2 ◽

2013 ◽

Vol 6 (3) ◽

pp. 263-271 ◽

Cited By ~ 17

Author(s):

Bikram Sharma ◽

Megan D. Ramus ◽

Christopher T. Kirkwood ◽

Emma E. Sperry ◽

Pao-Hsien Chu ◽

...

Keyword(s):

Angiogenic Activity ◽

Specific Manner ◽

Context Specific

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Observation of others’ threat reactions recovers memories previously shaped by firsthand experiences

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2101290118 ◽

2021 ◽

Vol 118 (30) ◽

pp. e2101290118

Author(s):

Jan Haaker ◽

Lorenzo Diaz-Mataix ◽

Gemma Guillazo-Blanch ◽

Sara A. Stark ◽

Lea Kern ◽

...

Keyword(s):

Defensive Behavior ◽

Physiological Responses ◽

Associative Memories ◽

Specific Manner ◽

Analogous Experiment ◽

Human Participants ◽

Context Specific ◽

Conditioned Cues

Information about dangers can spread effectively by observation of others’ threat responses. Yet, it is unclear if such observational threat information interacts with associative memories that are shaped by the individual’s direct, firsthand experiences. Here, we show in humans and rats that the mere observation of a conspecific’s threat reactions reinstates previously learned and extinguished threat responses in the observer. In two experiments, human participants displayed elevated physiological responses to threat-conditioned cues after observational reinstatement in a context-specific manner. The elevation of physiological responses (arousal) was further specific to the context that was observed as dangerous. An analogous experiment in rats provided converging results by demonstrating reinstatement of defensive behavior after observing another rat’s threat reactions. Taken together, our findings provide cross-species evidence that observation of others’ threat reactions can recover associations previously shaped by direct, firsthand aversive experiences. Our study offers a perspective on how retrieval of threat memories draws from associative mechanisms that might underlie both observations of others’ and firsthand experiences.

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Global analysis of the RpaB regulon based on the positional distribution of HLR1 sequences and comparative differential RNA-Seq data

10.1101/443713 ◽

2018 ◽

Author(s):

Matthias Riediger ◽

Taro Kadowaki ◽

Ryuta Nagayama ◽

Jens Georg ◽

Yukako Hihara ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Transcriptional Activation ◽

Target Genes ◽

Global Analysis ◽

Affinity Purification ◽

Electron Flow ◽

Positional Distribution ◽

State Transitions ◽

Northern Hybridization

ABSTRACTThe transcription factor RpaB regulates the expression of genes encoding photosynthesis-associated proteins during light acclimation. The binding site of RpaB is the HLR1 motif, a pair of imperfect octameric direct repeats, separated by two random nucleotides. Here, we used high-resolution mapping data of transcriptional start sites (TSSs) in the modelSynechocystissp. PCC 6803 in conjunction with the positional distribution of HLR1 sites for the global prediction of the RpaB regulon. The results demonstrate that RpaB regulates the expression of more than 150 promoters, driving the transcription of protein-coding and non-coding genes and antisense transcripts under low light and upon the shift to high light when DNA binding activity is lost. Transcriptional activation by RpaB is achieved when the HLR1 motif is located 66 to 45 nt upstream, repression occurs when it is close to or overlapping the TSS. Selected examples were validated by multiple experimental approaches, including chromatin affinity purification, reporter gene, northern hybridization and electrophoretic mobility shift assays. We found that RpaB controlsssr2016/pgr5, which is involved in cyclic electron flow and state transitions; six out of nine ferredoxins; three of four FtsH proteases;gcvP/slr0293, encoding a crucial photorespiratory protein; andnirAandisiAfor which we suggest cross-regulation with the transcription factors NtcA or FurA, respectively. In addition to photosynthetic gene functions, RpaB contributes to the control of genes affiliated with nitrogen assimilation, cofactor biosyntheses, the CRISPR system and the circadian clock, making it one of the most versatile regulators in cyanobacteria.Significance StatementRpaB is a transcription factor in cyanobacteria and in the chloroplasts of several lineages of eukaryotic algae. Like other important transcription factors, the gene encoding RpaB cannot be deleted, making the study of deletion mutants impossible. Based on a bioinformatic approach, we increased the number of known genes controlled by RpaB by a factor of 5. Depending on the distance to the TSS, RpaB mediates transcriptional activation or repression. The high number and functional diversity among its target genes and co-regulation with other transcriptional regulators characterize RpaB as a regulatory hub.

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