LEPR lineage cells in CAF development and the regulatory role of the KLF1 transcription factor in CRC CAF function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA906050 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22427619_1.fastq.gz | Fastqsanger.gz | |||
| SRR22427619_2.fastq.gz | Fastqsanger.gz | |||
| SRR22427620_1.fastq.gz | Fastqsanger.gz | |||
| SRR22427620_2.fastq.gz | Fastqsanger.gz | |||
| SRR22427621_1.fastq.gz | Fastqsanger.gz |
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Project description:In this project we did a proteomic analysis from iPSCs-derived macrophages with the activation of thranscription factor KLF1, upon tamoxifen induction. These macrophages are a model for the study of the erythroid island (EI) niche in adult hematopoietic tissues, such as bone marrow and spleen. We wanted to assess the upregulated proteins in macrophages upon KLF1 activation to further study the interactions between macrophages and erythroid cells whithin the EI niche.
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Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.
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Project description:KLF1 (EKLF) regulates a diverse suite of genes to direct erythroid cell differentiation from bi-potent progenitors. To determine the local cis-regulatory contexts and transcription factor networks in which KLF1 operates, we performed KLF1 ChIP-seq in the mouse. We found at least 945 sites in the genome of E14.5 fetal liver erythroid cells which are occupied by endogenous KLF1. Many of these recovered sites reside in erythroid gene promoters such as β-globin, but the majority are distant to any known gene. Our data suggests KLF1 directly regulates most aspects of terminal erythroid differentiation including production of α and β-globin protein chains, heme biosynthesis, co-ordination of proliferation and anti-apoptotic pathways, and construction of the red cell membrane and cytoskeleton by functioning primarily as a transcriptional activator. Additionally, we suggest new mechanisms for KLF1 co-operation with other transcription factors, in particular the erythroid transcription factor GATA1, to maintain homeostasis in the erythroid compartment. Examination of KLF1 occupancy in primary erythroid cells. KLF1-ChIP and input samples were run on AB SOLiD Systems 2.0 and 3.0. The genomic alignment files (*sorted.txt) and peak file (*bed) contain the combined System 2.0 and 3.0 data.
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