scholarly journals EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

2020 ◽  
Vol 21 (5) ◽  
pp. 1664 ◽  
Author(s):  
Emmanuelle Havis ◽  
Delphine Duprez
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factor ◽  
Connective Tissue ◽  
Transcriptional Activity ◽  
Tendon Repair ◽  
Regulatory Elements ◽  
Biological Functions ◽  
Connective Tissues ◽  
Post Translational Modifications ◽  
Matrix Production

Although the transcription factor EGR1 is known as NGF1-A, TIS8, Krox24, zif/268, and ZENK, it still has many fewer names than biological functions. A broad range of signals induce Egr1 gene expression via numerous regulatory elements identified in the Egr1 promoter. EGR1 is also the target of multiple post-translational modifications, which modulate EGR1 transcriptional activity. Despite the myriad regulators of Egr1 transcription and translation, and the numerous biological functions identified for EGR1, the literature reveals a recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix. Egr1 is expressed in different connective tissues, such as tendon (a dense connective tissue), cartilage and bone (supportive connective tissues), and adipose tissue (a loose connective tissue). Egr1 is involved in the development, homeostasis, and healing processes of these tissues, mainly via the regulation of extracellular matrix. In addition, Egr1 is often involved in the abnormal production of extracellular matrix in fibrotic conditions, and Egr1 deletion is seen as a target for therapeutic strategies to fight fibrotic conditions. This generic EGR1 function in matrix regulation has little-explored implications but is potentially important for tendon repair.

Abstract 311: Osteogenic Transcription Factor Runx2 Represses Connective Tissue Growth Factor Gene Expression And TGFβ Signaling In Vascular Smooth Muscle Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Toru Tanaka ◽  
Takehisa Shimizu ◽  
Norimichi Koitabashi ◽  
Hiroki Matsui ◽  
Hiroshi Doi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Connective Tissue ◽  
Vascular Smooth Muscle Cells ◽  
Tissue Growth ◽  
Matrix Synthesis ◽  
Tgfβ Signaling

[Objective] Runx2, a key transcription factor in osteoblast differentiation, is expressed in calcified atherosclerotic plaques. We have recently shown that Runx2 represses vascular smooth muscle cells (VSMCs) differentiation and promotes their osteogenic differentiation. Connective tissue growth factor (CTGF) has been implicated in the progression to vulnerable plaque by inducing mononuclear cell chemotaxis and VSMCs apoptosis despite of its potent stimulatory effect on connective tissue cell the proliferation and extracellular matrix synthesis. To assess the role of Runx2 in the process of plaque development, we investigated the molecular mechanism of the CTGF gene expression by Runx2 in VSMCs. [Methods and Results] RT-PCR analyses showed that adenovirally overexpressed Runx2 significantly repressed the basal expression of the CTGF gene in human aortic SMCs (HASMCs). Consistent with this, knockdown of the Runx2 expression in HASMCs by small interfering RNA (siRNA) increased CTGF mRNA levels. Luciferase assays showed that Runx2 reduced the transcriptional activity of the CTGF promoter. Transfection of a series of 5′-deletion constructs revealed that Runx2 inhibited CTGF expression through the sequence element located at 5′ untranslated region of CTGF mRNA. We next examined the effects of Runx2 on the TGFβ-induced CTGF expression. Runx2 overexpression significantly repressed CTGF expression in HASMCs stimulated with TGFβ, and knockdown of Runx2 by siRNA enhanced the induction of CTGF expression in response to TGFβ. Runx2 repressed TGFβ-induced CTGF promoter activity through the sequence including Smad binding element (SBE). Overexpression of Runx2 significantly reduced TGFβ- and Smad3-mediated luciferase activity of Smad-dependent promoter which contains four copies of SBE. Biotinylated DNA pulldown assay using SBE of CTGF promoter showed that Runx2 formed a complex with Smad3 and Smad4. [Conclusion] Runx2 repressed basal and TGFβ-induced CTGF gene expression in VSMCs. Thus, in addition to the potential for inducing vascular calcification, Runx2 may affect plaque stability by modulating extracellular matrix synthesis through inhibiting CTGF gene expression and TGFβ signaling.

scholarly journals Insight into GATA1 transcriptional activity through interrogation of cis elements disrupted in human erythroid disorders

2016 ◽  
Vol 113 (16) ◽  
pp. 4434-4439 ◽  
Author(s):  
Aoi Wakabayashi ◽  
Jacob C. Ulirsch ◽  
Leif S. Ludwig ◽  
Claudia Fiorini ◽  
Makiko Yasuda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activity ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Targeted Disruption ◽  
Altered Gene Expression ◽  
Whole Exome ◽  
Altered Gene ◽  
Insight Into

Whole-exome sequencing has been incredibly successful in identifying causal genetic variants and has revealed a number of novel genes associated with blood and other diseases. One limitation of this approach is that it overlooks mutations in noncoding regulatory elements. Furthermore, the mechanisms by which mutations in transcriptional cis-regulatory elements result in disease remain poorly understood. Here we used CRISPR/Cas9 genome editing to interrogate three such elements harboring mutations in human erythroid disorders, which in all cases are predicted to disrupt a canonical binding motif for the hematopoietic transcription factor GATA1. Deletions of as few as two to four nucleotides resulted in a substantial decrease (>80%) in target gene expression. Isolated deletions of the canonical GATA1 binding motif completely abrogated binding of the cofactor TAL1, which binds to a separate motif. Having verified the functionality of these three GATA1 motifs, we demonstrate strong evolutionary conservation of GATA1 motifs in regulatory elements proximal to other genes implicated in erythroid disorders, and show that targeted disruption of such elements results in altered gene expression. By modeling transcription factor binding patterns, we show that multiple transcription factors are associated with erythroid gene expression, and have created predictive maps modeling putative disruptions of their binding sites at key regulatory elements. Our study provides insight into GATA1 transcriptional activity and may prove a useful resource for investigating the pathogenicity of noncoding variants in human erythroid disorders.

scholarly journals Selective association of an endogenous lectin with connective tissues

1985 ◽  
Vol 73 (1) ◽  
pp. 347-359
Author(s):  
J.W. Catt ◽  
F.L. Harrison
Keyword(s):  
Extracellular Matrix ◽  
Connective Tissue ◽  
Heart Tissue ◽  
Hair Follicles ◽  
Connective Tissues ◽  
Alveolar Cells ◽  
Tissue Sections ◽  
Liver And Kidney ◽  
Endogenous Lectins ◽  
Or Organization

Using indirect immunofluorescence we have localized an endogenous beta-galactoside-specific lectin in resin-embedded rabbit tissue sections. The pattern of lectin distribution correlates well with biochemical estimations of lectin levels, being abundant in intestine, lung and heart tissue and relatively less abundant in skeletal muscle, liver and kidney. In all tissues lectin is found in connective tissue associated with fibroblasts and the extracellular matrix, and at the periphery of morphologically recognizable smooth muscle cells. The lectin is abundant in skin, intestine and blood vessels, where connective tissue forms the tissue architecture. It is also abundant in heart, where it is particularly associated with the capillaries and lung, where it is also found in alveolar cells. Discrete localization of lectin occurs in areas of connective tissue where epithelial elements are differentiating, such as the crypts of Lieberkuhns in the small intestine and hair follicles in the skin. From these observations we suggest that in cells of mesenchymal origin these endogenous lectins may play a role in the elaboration or organization of the extracellular matrix that regulates tissue differentiation in a number of embryonic and adult tissues.

scholarly journals Single-cell-resolved dynamics of chromatin architecture delineate cell and regulatory states in wildtype and cloche/npas4l mutant zebrafish embryos

2020 ◽  
Author(s):  
Alison C. McGarvey ◽  
Wolfgang Kopp ◽  
Dubravka Vučićević ◽  
Rieke Kempfer ◽  
Kenny Mattonet ◽  
...  
Keyword(s):  
Single Cell ◽  
Transcriptional Activity ◽  
Regulatory Elements ◽  
Zebrafish Embryos ◽  
Computational Tool ◽  
Post Translational Modifications ◽  
Future Studies ◽  
3D Genome ◽  
Dna Accessibility ◽  
Intricate Mechanism

DNA accessibility of cis regulatory elements (CREs) dictates transcriptional activity and drives cell differentiation during development. While many of the genes that regulate embryonic development have been described, the underlying CRE dynamics controlling their expression remain largely unknown. To address this, we applied single-cell combinatorial indexing ATAC-seq (sci-ATAC-seq) to whole 24 hours post fertilization (hpf) stage zebrafish embryos and developed a new computational tool, ScregSeg, that selects informative genome segments and classifies complex accessibility dynamics. We integrated the ScregSeg output with bulk measurements for histone post-translational modifications and 3D genome organization, expanding knowledge of regulatory principles between chromatin modalities. Sci-ATAC-seq profiling of npas4l/cloche mutant embryos revealed novel cellular roles for this hemato-vascular transcriptional master regulator and suggests an intricate mechanism regulating its expression. Our work constitutes a valuable resource for future studies in developmental, molecular, and computational biology.

scholarly journals The transcription factor GLI1 cooperates with the chromatin remodeler SMARCA2 to regulate chromatin accessibility at distal DNA regulatory elements

2020 ◽  
Vol 295 (26) ◽  
pp. 8725-8735
Author(s):  
Stephanie L. Safgren ◽  
Rachel L. O. Olson ◽  
Anne M. Vrabel ◽  
Luciana L. Almada ◽  
David L. Marks ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Micrococcal Nuclease ◽  
Gene Promoters ◽  
Interacting Protein ◽  
Transcriptional Activation Domain ◽  
Dna Regulatory Elements

The transcription factor GLI1 (GLI family zinc finger 1) plays a key role in the development and progression of multiple malignancies. To date, regulation of transcriptional activity at target gene promoters is the only molecular event known to underlie the oncogenic function of GLI1. Here, we provide evidence that GLI1 controls chromatin accessibility at distal regulatory regions by modulating the recruitment of SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2) to these elements. We demonstrate that SMARCA2 endogenously interacts with GLI1 and enhances its transcriptional activity. Mapping experiments indicated that the C-terminal transcriptional activation domain of GLI1 and SMARCA2's central domains, including its ATPase motif, are required for this interaction. Interestingly, similar to SMARCA2, GLI1 overexpression increased chromatin accessibility, as indicated by results of the micrococcal nuclease assay. Further, results of assays for transposase-accessible chromatin with sequencing (ATAC-seq) after GLI1 knockdown supported these findings, revealing that GLI1 regulates chromatin accessibility at several regions distal to gene promoters. Integrated RNA-seq and ATAC-seq data analyses identified a subset of differentially expressed genes located in cis to these regulated chromatin sites. Finally, using the GLI1-regulated gene HHIP (Hedgehog-interacting protein) as a model, we demonstrate that GLI1 and SMARCA2 co-occupy a distal chromatin peak and that SMARCA2 recruitment to this HHIP putative enhancer requires intact GLI1. These findings provide insights into how GLI1 controls gene expression in cancer cells and may inform approaches targeting this oncogenic transcription factor to manage malignancies.

A Congenital Anemia Reveals Distinct Targeting Mechanisms for Master Transcription Factor GATA1

Blood ◽  
2022 ◽  
Author(s):  
Leif Ludwig ◽  
Caleb A Lareau ◽  
Erik L. Bao ◽  
Nan Liu ◽  
Taiju Utsugisawa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cellular Differentiation ◽  
Transcriptional Activity ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Mechanisms ◽  
Red Cell ◽  
Missense Mutations ◽  
Master Regulators ◽  
Intrinsically Disordered

Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.

scholarly journals The Roles of Post-Translational Modifications in STAT3 Biological Activities and Functions

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 956
Author(s):  
Annachiara Tesoriere ◽  
Alberto Dinarello ◽  
Francesco Argenton
Keyword(s):  
Transcription Factor ◽  
Cancer Progression ◽  
Transcriptional Activity ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Cellular Models ◽  
Stat3 Phosphorylation ◽  
Cellular Context ◽  
Cell Growth And Proliferation

STAT3 is an important transcription factor that regulates cell growth and proliferation by regulating gene transcription of a plethora of genes. This protein also has many roles in cancer progression and several tumors such as prostate, lung, breast, and intestine cancers that are characterized by strong STAT3-dependent transcriptional activity. This protein is post-translationally modified in different ways according to cellular context and stimulus, and the same post-translational modification can have opposite effects in different cellular models. In this review, we describe the studies performed on the main modifications affecting the activity of STAT3: phosphorylation of tyrosine 705 and serine 727; acetylation of lysine 49, 87, 601, 615, 631, 685, 707, and 709; and methylation of lysine 49, 140, and 180. The extensive results obtained by different studies demonstrate that post-translational modifications drastically change STAT3 activities and that we need further analysis to properly elucidate all the functions of this multifaceted transcription factor.

Balance between bacterial extracellular matrix production and intramacrophage proliferation by a Salmonella ‐specific SPI‐2 encoded transcription factor

2021 ◽  
Author(s):  
María Laura Echarren ◽  
Nicolás R. Figueroa ◽  
Luisina Vitor‐Horen ◽  
M. Graciela Pucciarelli ◽  
Francisco García‐del Portillo ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factor ◽  
Extracellular Matrix Production ◽  
Matrix Production
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