Lineage-Specific Mitotic Bookmarking by Hematopoietic Transcription Factor GATA1

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 547-547
Author(s):  
Stephan Kadauke ◽  
Jan M Pawlicki ◽  
Maheshi Udugama ◽  
Jordan C Achtman ◽  
Yong Cheng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Target Genes ◽  
Confocal Imaging ◽  
Erythroid Precursor ◽  
Cell Divisions ◽  
A Genome ◽  
Target Sites ◽  
Lineage Stability ◽  
Mitotic Chromatin

Abstract Abstract 547 Hematopoietic lineage choice decisions are stably maintained throughout many cell divisions. For example, erythroid precursor cells undergo several rounds of cell division during their maturation. During each mitosis, most transcription factors separate from chromatin causing transcription to cease globally. Mitosis therefore poses a challenge for transcription factors to re-associate with the appropriate target sites in chromatin of newborn cells. The epigenetic mechanisms that cement lineage stability and resist cell reprogramming during mitosis are poorly understood, although recent evidence supports the existence of “bookmarking” factors that remain bound to mitotic chromatin. Since the hematopoietic transcription factor GATA1 controls the expression of essentially all erythroid-specific genes, we asked whether it might play a role in maintaining erythroid gene expression programs throughout the cell cycle. Live cell confocal imaging revealed that foci of high GATA1 density are present within mitotic chromatin. Using a novel approach that combines mitotic cell sorting with ChIP-Seq, we defined mitotic GATA1 binding sites on a genome-wide scale. Remarkably, whereas GATA1 vacated the great majority of its target sites during mitosis, including the archetypical GATA1 regulated genes α- and β-globin, those target sites where GATA1 was maintained during mitosis showed a strong tendency to reside near genes encoding key developmental regulators of hematopoiesis (e.g., Zfpm1, Nfe2, Klf1, Gata1, Gata2, Runx1). Tissue-specific GATA1 co-regulators such as FOG-1 and the SCL complex dissociated from GATA1-occupied elements during mitosis, suggesting that GATA1 persists at these sites to facilitate their spatially and temporally appropriate reassembly upon exit from mitosis. Consistent with the notion that GATA1 acts as a mitotic bookmark for its mitotic target genes, timed primary transcript analysis revealed that genes that are marked by GATA1 during mitosis re-activate more rapidly upon G1 entry than those that are not. To directly address the functional importance of mitotic chromatin binding, we developed a version of GATA1 that is selectively degraded during mitosis but remains stable during interphase. This strategy allowed us to prove, for the first time, that the presence of a transcription factor is required specifically during mitosis for timely reactivation of its mitotic target genes. In addition, mitotically disrupted GATA1 failed to fully repress markers of immature erythroid precursors (e.g., Kit, Lyl1), highlighting a potential role of mitotic GATA1 bookmarking for establishing and maintaining lineage- and developmental stage-specific transcriptional programs. Follow-up mechanistic experiments to define the mode by which GATA1 operates during mitosis are underway and will be discussed at the meeting. Together, these studies establish GATA1 as a bona fide mitotic bookmarking factor and provide a deeper understanding by which transcription programs are faithfully perpetuated through cell divisions to maintain lineage stability. Disclosures: No relevant conflicts of interest to declare.

A Potential Epigenetic Bookmarking Function for the Hematopoietic Transcription Factor GATA-1.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2601-2601
Author(s):  
Stephan Kadauke ◽  
Janine M Lamonica ◽  
Alan Lau ◽  
Margaret Chou ◽  
Gerd Blobel
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
High Throughput Sequencing ◽  
Conflicts Of Interest ◽  
Erythroid Differentiation ◽  
Regulatory Elements ◽  
Chromatin Binding ◽  
Erythroid Precursor ◽  
Lineage Stability ◽  
Mitotic Chromatin

Abstract Abstract 2601 Hematopoietic lineage choice decisions are stably maintained through many cell divisions. For example, erythroid precursor cells undergo several rounds of cell division during their maturation. During each mitosis, most transcription factors separate from chromatin causing transcription to cease globally. Mitosis therefore poses a challenge for transcription factors to re-associate with the appropriate target sites in chromatin of newborn cells. The epigenetic mechanisms that cement lineage stability and resist cell reprogramming during mitosis are poorly understood, although recent evidence supports the idea that “bookmarking” factors that remain associated with mitotic chromatin may play a role in this process. We therefore investigated whether the hematopoietic transcription factor GATA-1 might be retained at specific sites during mitosis. GATA-1 controls the expression of essentially all erythroid-specific genes and might therefore play a role in maintaining erythroid gene expression programs throughout the cell cycle. Surprisingly, we found that while a substantial fraction of GATA-1 dissociates from chromatin in mitosis, foci of high GATA-1 density are present within mitotic chromatin. To determine the exact locations of GATA-1 binding during mitosis, we developed a method to highly purify mitotic erythroid cells in sufficient quantities for chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq). These experiments revealed that a subset of sites bound by GATA-1 during interphase is occupied continuously throughout mitosis. Importantly, continuously GATA-1-occupied sites are enriched at promoters and cis-regulatory elements of genes coding for key developmental regulators of hematopoiesis (e.g., Fog1/Zfpm1, Gata2, Lyl1) but are notably absent at erythroid physiological and structural genes (e.g., Hba, Hbb, Epb4.9). To examine the importance of mitotic chromatin binding by GATA-1, we engineered a version of GATA-1 bearing a mitosis-specific degron that targets GATA-1 for degradation during mitosis but not interphase. Preliminary results show that mitotically degraded GATA-1 fails to induce differentiation when expressed in GATA-1-null erythroblasts. This suggests an important mitotic function for GATA-1. Current work focuses on delineating the mechanism by which continuous chromatin occupancy of GATA-1 throughout mitosis ensures proper erythroid differentiation. The results will be presented and discussed at the meeting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Th1 cell regulatory circuitry is largely conserved between human and mouse

2021 ◽  
Vol 4 (11) ◽  
pp. e202101075
Author(s):  
Stephen Henderson ◽  
Venu Pullabhatla ◽  
Arnulf Hertweck ◽  
Emanuele de Rinaldis ◽  
Javier Herrero ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Infectious Diseases ◽  
Binding Sites ◽  
Target Genes ◽  
Specific Gene ◽  
Type I ◽  
A Genome ◽  
Species Specific

Gene expression programs controlled by lineage-determining transcription factors are often conserved between species. However, infectious diseases have exerted profound evolutionary pressure, and therefore the genes regulated by immune-specific transcription factors might be expected to exhibit greater divergence. T-bet (Tbx21) is the immune-specific, lineage-specifying transcription factor for T helper type I (Th1) immunity, which is fundamental for the immune response to intracellular pathogens but also underlies inflammatory diseases. We compared T-bet genomic targets between mouse and human CD4+ T cells and correlated T-bet binding patterns with species-specific gene expression. Remarkably, we found that the majority of T-bet target genes are conserved between mouse and human, either via preservation of binding sites or via alternative binding sites associated with transposon-linked insertion. Species-specific T-bet binding was associated with differences in transcription factor–binding motifs and species-specific expression of associated genes. These results provide a genome-wide cross-species comparison of Th1 gene regulation that will enable more accurate translation of genetic targets and therapeutics from pre-clinical models of inflammatory and infectious diseases and cancer into human clinical trials.

scholarly journals Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8193
Author(s):  
Daniel Pérez-Cremades ◽  
Ana B. Paes ◽  
Xavier Vidal-Gómez ◽  
Ana Mompeón ◽  
Carlos Hermenegildo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Mirna Target ◽  
Target Genes ◽  
Functional Characterization ◽  
Human Endothelial Cells ◽  
Mrna Targets ◽  
Canonical Pathways

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.

Autoregulated Expression of Schizosaccharomyces pombe Meiosis-Specific Transcription Factor Mei4 and a Genome-Wide Search for Its Target Genes

Genetics ◽  
2000 ◽  
Vol 154 (4) ◽  
pp. 1497-1508 ◽  
Author(s):  
Hiroko Abe ◽  
Chikashi Shimoda
Keyword(s):  
Transcription Factor ◽  
Schizosaccharomyces Pombe ◽  
Target Genes ◽  
Northern Blotting ◽  
Forkhead Transcription Factor ◽  
Gene Encoding ◽  
Putative Promoter Region ◽  
Cis Acting ◽  
A Genome ◽  
Genome Wide Search

Abstract The Schizosaccharomyces pombe mei4+ gene encoding a forkhead transcription factor is necessary for the progression of meiosis and sporulation. We searched for novel meiotic genes, the expression of which is dependent on Mei4p, since only the spo6+ gene has been assigned to its targets. Six known genes responsible for meiotic recombination were examined by Northern blotting, but none were Mei4 dependent for transcription. We determined the important cis-acting element, designated FLEX, to which Mei4p can bind. The S. pombe genome sequence database (The Sanger Centre, UK) was scanned for the central core heptamer and its flanking 3′ sequence of FLEX composed of 17 nucleotides, and 10 candidate targets of Mei4 were selected. These contained a FLEX-like sequence in the 5′ upstream nontranslatable region within 1 kb of the initiation codon. Northern blotting confirmed that 9 of them, named mde1+ to mde9+, were transcriptionally induced during meiosis and were dependent on mei4+. Most mde genes have not been genetically defined yet, except for mde9+, which is identical to spn5+, which encodes one of the septin family of proteins. mde3+ and a related gene pit1+ encode proteins related to Saccharomyces cerevisiae Ime2. The double disruptant frequently produced asci having an abnormal number and size of spores, although it completed meiosis. We also found that the forkhead DNA-binding domain of Mei4p binds to the FLEX-like element in the putative promoter region of mei4 and that the maximum induction level of mei4 mRNA required functional mei4 activity. Furthermore, expression of a reporter gene driven by the authentic mei4 promoter was induced in vegetative cells by ectopic overproduction of Mei4p. These results suggest that mei4 transcription is positively autoregulated.

scholarly journals Global Analysis of the Genetic Variations in miRNA-Targeted Sites and Their Correlations With Agronomic Traits in Rapeseed

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengfei Xu ◽  
Yantao Zhu ◽  
Yanfeng Zhang ◽  
Jianxia Jiang ◽  
Liyong Yang ◽  
...  
Keyword(s):  
Mirna Target ◽  
Target Genes ◽  
Rare Variants ◽  
Agronomic Traits ◽  
Global Analysis ◽  
Variant Calling ◽  
Genetic Variations ◽  
Nucleotide Polymorphisms ◽  
A Genome ◽  
Target Sites

MicroRNAs (miRNAs) and their target genes play vital roles in crops. However, the genetic variations in miRNA-targeted sites that affect miRNA cleavage efficiency and their correlations with agronomic traits in crops remain unexplored. On the basis of a genome-wide DNA re-sequencing of 210 elite rapeseed (Brassica napus) accessions, we identified the single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELs) in miRNA-targeted sites complementary to miRNAs. Variant calling revealed 7.14 million SNPs and 2.89 million INDELs throughout the genomes of 210 rapeseed accessions. Furthermore, we detected 330 SNPs and 79 INDELs in 357 miRNA target sites, of which 33.50% were rare variants. We also analyzed the correlation between the genetic variations in miRNA target sites and 12 rapeseed agronomic traits. Eleven SNPs in miRNA target sites were significantly correlated with phenotypes in three consecutive years. More specifically, three correlated SNPs within the miRNA-binding regions of BnSPL9-3, BnSPL13-2, and BnCUC1-2 were in the loci associated with the branch angle, seed weight, and silique number, respectively; expression profiling suggested that the variation at these 3 miRNA target sites significantly affected the expression level of the corresponding target genes. Taken together, the results of this study provide researchers and breeders with a global view of the genetic variations in miRNA-targeted sites in rapeseed and reveal the potential effects of these genetic variations on elite agronomic traits.

scholarly journals Unification of Opposites between Two Antioxidant Transcription Factors Nrf1 and Nrf2 in Mediating Distinct Cellular Responses to the Endoplasmic Reticulum Stressor Tunicamycin

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 4 ◽  
Author(s):  
Yu-ping Zhu ◽  
Ze Zheng ◽  
Shaofan Hu ◽  
Xufang Ru ◽  
Zhuo Fan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Er Stress ◽  
Target Genes ◽  
Cellular Responses ◽  
Water Soluble ◽  
Heme Oxygenase 1 ◽  
Nuclear Factor ◽  
Activating Transcription Factor

The water-soluble Nrf2 (nuclear factor, erythroid 2-like 2, also called Nfe2l2) is accepted as a master regulator of antioxidant responses to cellular stress, and it was also identified as a direct target of the endoplasmic reticulum (ER)-anchored PERK (protein kinase RNA-like endoplasmic reticulum kinase). However, the membrane-bound Nrf1 (nuclear factor, erythroid 2-like 1, also called Nfe2l1) response to ER stress remains elusive. Herein, we report a unity of opposites between these two antioxidant transcription factors, Nrf1 and Nrf2, in coordinating distinct cellular responses to the ER stressor tunicamycin (TU). The TU-inducible transcription of Nrf1 and Nrf2, as well as GCLM (glutamate cysteine ligase modifier subunit) and HO-1 (heme oxygenase 1), was accompanied by activation of ER stress signaling networks. Notably, the unfolded protein response (UPR) mediated by ATF6 (activating transcription factor 6), IRE1 (inositol requiring enzyme 1) and PERK was significantly suppressed by Nrf1α-specific knockout, but hyper-expression of Nrf2 and its target genes GCLM and HO-1 has retained in Nrf1α−/− cells. By contrast, Nrf2−/−ΔTA cells with genomic deletion of its transactivation (TA) domain resulted in significant decreases of GCLM, HO-1 and Nrf1; this was accompanied by partial decreases of IRE1 and ATF6, rather than PERK, but with an increase of ATF4 (activating transcription factor 4). Interestingly, Nrf1 glycosylation and its trans-activity to mediate the transcriptional expression of the 26S proteasomal subunits, were repressed by TU. This inhibitory effect was enhanced by Nrf1α−/− and Nrf2−/−ΔTA, but not by a constitutive activator caNrf2ΔN (that increased abundances of the non-glycosylated and processed Nrf1). Furthermore, caNrf2ΔN also enhanced induction of PERK and IRE1 by TU, but reduced expression of ATF4 and HO-1. Thus, it is inferred that such distinct roles of Nrf1 and Nrf2 are unified to maintain cell homeostasis by a series of coordinated ER-to-nuclear signaling responses to TU. Nrf1α (i.e., a full-length form) acts in a cell-autonomous manner to determine the transcription of most of UPR-target genes, albeit Nrf2 is also partially involved in this process. Consistently, transactivation of ARE (antioxidant response element)-driven BIP (binding immunoglobulin protein)-, PERK- and XBP1 (X-box binding protein 1)-Luc reporter genes was mediated directly by Nrf1 and/or Nrf2. Interestingly, Nrf1α is more potent than Nrf2 at mediating the cytoprotective responses against the cytotoxicity of TU alone or plus tBHQ (tert-butylhydroquinone). This is also further supported by the evidence that the intracellular reactive oxygen species (ROS) levels are increased in Nrf1α−/− cells, but rather are, to our surprise, decreased in Nrf2−/−ΔTA cells.

scholarly journals The TEA Transcription Factor Tec1 Confers Promoter-Specific Gene Regulation by Ste12-Dependent and -Independent Mechanisms

2010 ◽  
Vol 9 (4) ◽  
pp. 514-531 ◽  
Author(s):  
Barbara Heise ◽  
Julia van der Felden ◽  
Sandra Kern ◽  
Mario Malcher ◽  
Stefan Brückner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Target Genes ◽  
Specific Gene ◽  
Dependent Manner ◽  
A Genome ◽  
Regulated Gene Expression

ABSTRACT In Saccharomyces cerevisiae, the TEA transcription factor Tec1 is known to regulate target genes together with a second transcription factor, Ste12. Tec1-Ste12 complexes can activate transcription through Tec1 binding sites (TCSs), which can be further combined with Ste12 binding sites (PREs) for cooperative DNA binding. However, previous studies have hinted that Tec1 might regulate transcription also without Ste12. Here, we show that in vivo, physiological amounts of Tec1 are sufficient to stimulate TCS-mediated gene expression and transcription of the FLO11 gene in the absence of Ste12. In vitro, Tec1 is able to bind TCS elements with high affinity and specificity without Ste12. Furthermore, Tec1 contains a C-terminal transcriptional activation domain that confers Ste12-independent activation of TCS-regulated gene expression. On a genome-wide scale, we identified 302 Tec1 target genes that constitute two distinct classes. A first class of 254 genes is regulated by Tec1 in a Ste12-dependent manner and is enriched for genes that are bound by Tec1 and Ste12 in vivo. In contrast, a second class of 48 genes can be regulated by Tec1 independently of Ste12 and is enriched for genes that are bound by the stress transcription factors Yap6, Nrg1, Cin5, Skn7, Hsf1, and Msn4. Finally, we find that combinatorial control by Tec1-Ste12 complexes stabilizes Tec1 against degradation. Our study suggests that Tec1 is able to regulate TCS-mediated gene expression by Ste12-dependent and Ste12-independent mechanisms that enable promoter-specific transcriptional control.

scholarly journals Basic Helix-Loop-Helix (bHLH) Transcription Factors Regulate a Wide Range of Functions in Arabidopsis

2021 ◽  
Vol 22 (13) ◽  
pp. 7152
Author(s):  
Yaqi Hao ◽  
Xiumei Zong ◽  
Pan Ren ◽  
Yuqi Qian ◽  
Aigen Fu
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Target Genes ◽  
Gene Families ◽  
Bhlh Transcription Factor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Wide Range ◽  
Range Of Functions ◽  
Eukaryotic Organisms

The basic helix-loop-helix (bHLH) transcription factor family is one of the largest transcription factor gene families in Arabidopsis thaliana, and contains a bHLH motif that is highly conserved throughout eukaryotic organisms. Members of this family have two conserved motifs, a basic DNA binding region and a helix-loop-helix (HLH) region. These proteins containing bHLH domain usually act as homo- or heterodimers to regulate the expression of their target genes, which are involved in many physiological processes and have a broad range of functions in biosynthesis, metabolism and transduction of plant hormones. Although there are a number of articles on different aspects to provide detailed information on this family in plants, an overall summary is not available. In this review, we summarize various aspects of related studies that provide an overview of insights into the pleiotropic regulatory roles of these transcription factors in plant growth and development, stress response, biochemical functions and the web of signaling networks. We then provide an overview of the functional profile of the bHLH family and the regulatory mechanisms of other proteins.

scholarly journals Expresso: A database and web server for exploring the interaction of transcription factors and their target genes in Arabidopsis thaliana using ChIP-Seq peak data

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 372 ◽  
Author(s):  
Delasa Aghamirzaie ◽  
Karthik Raja Velmurugan ◽  
Shuchi Wu ◽  
Doaa Altarawy ◽  
Lenwood S. Heath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Data Sets ◽  
Motif Analysis ◽  
Chromatin Immunoprecipitation Sequencing

Motivation: The increasing availability of chromatin immunoprecipitation sequencing (ChIP-Seq) data enables us to learn more about the action of transcription factors in the regulation of gene expression. Even though in vivo transcriptional regulation often involves the concerted action of more than one transcription factor, the format of each individual ChIP-Seq dataset usually represents the action of a single transcription factor. Therefore, a relational database in which available ChIP-Seq datasets are curated is essential. Results: We present Expresso (database and webserver) as a tool for the collection and integration of available Arabidopsis ChIP-Seq peak data, which in turn can be linked to a user’s gene expression data. Known target genes of transcription factors were identified by motif analysis of publicly available GEO ChIP-Seq data sets. Expresso currently provides three services: 1) Identification of target genes of a given transcription factor; 2) Identification of transcription factors that regulate a gene of interest; 3) Computation of correlation between the gene expression of transcription factors and their target genes. Availability: Expresso is freely available at http://bioinformatics.cs.vt.edu/expresso/

scholarly journals Genome-wide reduction in chromatin accessibility and unique transcription factor footprints in endothelial cells and fibroblasts in scleroderma skin

2020 ◽  
Author(s):  
Pei-Suen Tsou ◽  
Pamela J. Palisoc ◽  
Mustafa Ali ◽  
Dinesh Khanna ◽  
Amr H Sawalha
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Target Genes ◽  
Critical Role ◽  
Vascular Complications ◽  
Chromatin Accessibility ◽  
Unknown Etiology ◽  
Healthy Controls ◽  
Genome Wide

AbstractSystemic sclerosis (SSc) is a rare autoimmune disease of unknown etiology characterized by widespread fibrosis and vascular complications. We utilized an assay for genome-wide chromatin accessibility to examine the chromatin landscape and transcription factor footprints in both endothelial cells (ECs) and fibroblasts isolated from healthy controls and patients with diffuse cutaneous (dc) SSc. In both cell types, chromatin accessibility was significantly reduced in SSc patients compared to healthy controls. Genes annotated from differentially accessible chromatin regions were enriched in pathways and gene ontologies involved in the nervous system. In addition, our data revealed that chromatin binding of transcription factors SNAI2, ETV2, and ELF1 was significantly increased in dcSSc ECs, while recruitment of RUNX1 and RUNX2 was enriched in dcSSc fibroblasts. Significant elevation of SNAI2 and ETV2 levels in dcSSc ECs, and RUNX2 levels in dcSSc fibroblasts were confirmed. Further analysis of publicly available ETV2-target genes suggests that ETV2 may play a critical role in EC dysfunction in dcSSc. Our data, for the first time, uncovered the chromatin blueprint of dcSSc ECs and fibroblasts, and suggested that neural-related characteristics of SSc ECs and fibroblasts could be a culprit for dysregulated angiogenesis and enhanced fibrosis. Targeting these pathways and the key transcription factors identified might present novel therapeutic approaches for this disease.

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