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Predicting Cis-Element Responses to Cell Signaling in Red Blood Cell Precursors [ER RNA-seq]

ABSTRACT: Chromatin signatures at cis-regulatory elements can predict how they regulate transcription. However, accurate cell type-specific prediction of functional cis-elements remains a significant computational challenge due to the lack of context regarding the role of environmental stimuli that may alter activity. Most existing datasets use static molecular and sequence features which do not evaluate cis-element responses to extracellular cues. To investigate chromatin changes mediated by Kit/SCF, we performed ATAC-seq and RNA-seq in acutely SCF stimulated HUDEP-2 cells and mapped enhancer-promoter interactions using existing datasets. The top Kit-predictive features included Inflammatory Response (JUN, JUND, ATF2, ATF3, EGR1), blood cell maintenance (RUNX1) and chromatin remodelers/transcription factors (THAP1, MXI1, PKNOX1, CTCF). EGR1 - a transcription factor which regulates proliferation and differentiation - was 37-fold upregulated after SCF treatment. Combined with ATAC-seq footprinting data, this suggested Kit transcriptional targets may be EGR1 dependent. To distinguish EGR1-sensitive from EGR1-insensitive KREs, we compared feature occupancy and selected evolutionarily conserved regions in each category. Understanding KREs' roles at a systems-level can also provide insights regarding how chromatin occupancy and transcription reorganizes signal responses. Dysfunctional KREs may contribute to chromatin misregulation in hematologic malignancies, or chemoresistance. any of our predicted KRE target genes have poorly described or unknown functions, which provide numerous in-roads to discover genetic, molecular, and cellular regulators of erythropoiesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314034 | GEO | 2026/05/27

REPOSITORIES: GEO

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Predicting Cis-Element Responses to Cell Signaling in Red Blood Cell Precursors [RNA-seq]

Project description:Chromatin signatures at cis-regulatory elements can predict how they regulate transcription. However, accurate cell type-specific prediction of functional cis-elements remains a significant computational challenge due to the lack of context regarding the role of environmental stimuli that may alter activity. Most existing datasets use static molecular and sequence features which do not evaluate cis-element responses to extracellular cues. To investigate chromatin changes mediated by Kit/SCF, we performed ATAC-seq and RNA-seq in acutely SCF stimulated HUDEP-2 cells and mapped enhancer-promoter interactions using existing datasets. The top Kit-predictive features included Inflammatory Response (JUN, JUND, ATF2, ATF3, EGR1), blood cell maintenance (RUNX1) and chromatin remodelers/transcription factors (THAP1, MXI1, PKNOX1, CTCF). EGR1 - a transcription factor which regulates proliferation and differentiation - was 37-fold upregulated after SCF treatment. Combined with ATAC-seq footprinting data, this suggested Kit transcriptional targets may be EGR1 dependent. To distinguish EGR1-sensitive from EGR1-insensitive KREs, we compared feature occupancy and selected evolutionarily conserved regions in each category. Understanding KREs' roles at a systems-level can also provide insights regarding how chromatin occupancy and transcription reorganizes signal responses. Dysfunctional KREs may contribute to chromatin misregulation in hematologic malignancies, or chemoresistance. any of our predicted KRE target genes have poorly described or unknown functions, which provide numerous in-roads to discover genetic, molecular, and cellular regulators of erythropoiesis.

2026-05-27 | GSE314032 | GEO

Predicting Cis-Element Responses to Cell Signaling in Red Blood Cell Precursors [ATAc-seq]

2026-05-27 | GSE314033 | GEO

Global phosphoproteomics elicited by the SCF/KIT axis in human skin mast cells unveil capicua as a potent KIT repressor

Project description:Global phosphoproteomics can reveal signaling cascades in unprecedented detail. The SCF/KIT axis represents a vital hematopoietic receptor tyrosine kinase (RTK) system with gain-of-function mutations prompting the development of mastocytosis and leukemia. Here, we employed a label-free phosphoproteomics profiling strategy to provide the first comprehensive portrayal of SCF-triggered phosphosignaling. Employing untransformed skin-derived mast cells expressing vast amounts of KIT, we uncover around 10,500 class-I-phosphosites following ligand-induced KIT dimerization. Apart from STAT5, the MEK/ERK cascade (including upstream and downstream events) stood out as highly stimulatable by SCF compared to less impacted PI3K/Akt>p38>JNK, a pattern validated by time-resolved immunoblotting. Direct comparison between MEK/ERKÕs and PI3KÕs support of basic programs (anti-apoptosis, cell cycle progression) revealed equipotency with substantial redundancy between the modules. In functional outputs, ERK showed dominance over PI3K regarding cytokine stimulation (TNF-a, IL-8, LIF, OSM) and was the only contributor in the induction of immediate early genes (Fos, JunB, Egr1). Our proteome-wide screen also found Å1,000 phosphosites currently undescribed in databases, pertaining to multiple protein classes. Among candidates, capicua (and components of its network) experienced massive phosphorylation by SCF. Perturbation with capicua by RNA interference unveiled its function as a potent KIT repressor, whose deregulation may contribute to the development of mastocytosis. We demonstrate the utility of an unbiased approach to uncover single protein entities and entire networks activated by RTKs, that can be surveyed experimentally. This rich resource enhances our understanding of RTK-elicited signaling networks and can serve as a benchmark to identify pathological processes, e.g. under circumstances of KIT deregulation.

2022-11-15 | PXD028252 | Pride

Global phosphoproteomics in SCF stimulated human skin mast cells

2022-03-31 | PXD028245 | Pride

CUT&Tag profiling of JUND chromatin binding in human mast cell line LAD2 under SCF stimulation and imatinib perturbation

Project description:Mast cells respond to cytokine cues through rapid transcriptional rewiring. Here we generated CUT&Tag profiles of the transcription factor JUND in the human mast cell line LAD2 under three culture conditions: SCF withdrawal (EM), SCF supplementation (SCF), and SCF withdrawal plus imatinib treatment (IM). Two biological replicates were collected for each condition. Libraries were sequenced as paired-end reads and processed by adapter/quality filtering, alignment to the human reference genome (GRCh38/hg38), peak calling, and generation of normalized genome browser tracks. This dataset provides a resource to examine how SCF signaling and c-KIT pathway inhibition reshape JUND occupancy in mast cells.

2026-01-14 | GSE316333 | GEO

Pulmonary fibroblast-derived stem cell factor promotes neutrophilic asthma by augmenting IL-17A production from ILC3s

Project description:Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.

2025-06-03 | GSE275251 | GEO

Genome-wide maps of Transcriptionalregulation of EGR1 transcription factor in iPAM cells.

Project description:We applied single-molecule sequencing and high-throughput analysis to analyze the regulation of EGR1 transcription in iPAM cells. By obtaining more than 4 billion base sequences from chromatin immunoprecipitation DNA, we generated a genome-wide chromatin state map of transcriptional regulation of EGR1 transcription factors in iPAM cells. Then, we analyzed the influence of EGR1 transcription regulation on macrophages by analyzing the binding position of EGR1 transcription factor to the genome.

2021-11-20 | GSE189087 | GEO

Genome-wide analysis of human bone marrow-derived MSC cells in comparision with MSC with EGR1 knockdown or EGR1 overexpressing cells

Project description:Analyze and compare the gene expression profile of human bone marrow derived-MSC in comparison with EGR1 knockdown or EGR1 overexpressing cells. The hypothesis was some genes were differentially expressed in these cell populations. Results provided important information regarding the gene expression difference by EGR1.

2021-11-21 | GSE122831 | GEO

Nicotinic acetylcholine receptors and EGF induce c-Kit ligand/Stem Cell Factor (SCF) in a β-arrestin-1 and E2F1 dependent manner in NSCLC

Project description:Lung cancer remains the leading cause of cancer-related deaths worldwide. β-arrestin-1 (ARRB1), a scaffolding protein involved in the termination or desensitization of signals arising from activated G-protein-coupled receptors (GPCRs) has been shown to play a role in invasion and proliferation of many cancers, including nicotine-induced proliferation of human non–small cell lung cancers (NSCLCs). In this study, we analyzed nicotine induced and β-arrestin-1 dependent genes from the microarray data. Our analysis show that SCF (Stem cell factor) strongly differentiated smokers from non-smokers implying an important role of this gene in NSCLCs. SCF, a major cytokine is the ligand for the c-Kit proto-oncogene. Here we elucidate the molecular mechanisms by which nicotine as well as EGF induces the expression of SCF in lung adenocarcinoma cell lines A549 and H1650. ChIP assays and transient transfection experiments showed that transcription factor E2F1 can positively regulate SCF expression at the transcriptional level; depletion of E2F1 or β-arrestin-1 prevented the nicotine-mediated induction of SCF. Given that the binding of SCF to c-Kit leads to activation of multiple downstream signaling pathways including Src, PI3K, MEK and EGFR pathways, our data suggest that the SCF plays a central role in lung carcinogenesis, and may be a potential therapeutic target for combating NSCLC. Studies presented here also provide evidence that SCF along with nicotine promotes self-renewal and proliferation of lung cancer stem cells (CSCs). Our findings reveal an important role and prognostic significance of SCF that can serve as a novel prognostic and predictive biomarker for NSCLC.

2013-11-10 | GSE44617 | GEO

Genome-wide maps of EGR1 binding in mouse frontal cortex

Project description:With anti-EGR1 immunoprecipitated chromatin from mouse prefrontal cortices, we generated EGR1 binding maps with 12, 014 high-confidence peaks. Approximately 81% of EGR1 peaks were within genic regions or nearby promoters, and over 45% EGR1 peaks were in the proximal promoter regions within 1 kb from transcription starting sites.

2019-07-31 | GSE67482 | GEO

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