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ChIP-seq of H3K27acethylation of human aortic endothelial cells (HAECs) treated with Cobalt chloride (CoCl2)

ABSTRACT: ChIP-seq of H3K27acethylation of human aortic endothelial cells (HAECs) treated with Cobalt chloride (CoCl2)

PROVIDER: PRJNA781450 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16973845.fastq.gz	Fastqsanger.gz
	SRR16973845_1.fastq.gz	Fastqsanger.gz
	SRR16973845_2.fastq.gz	Fastqsanger.gz
	SRR16973846.fastq.gz	Fastqsanger.gz
	SRR16973846_1.fastq.gz	Fastqsanger.gz

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Project description:Using the orthotopic breast cancer xenograft model of basal-like breast cancer MDA-MB-231 line, we have found that the expression of miRNAs encoded by MIR17HG was significantly decreased in cells isolated from spontaneous lung metastases compared to cells from primary tumors grown in orthotopic sites. We investigated the role of a MIR17HG family member, miR-18a, in primary tumor growth and pulmonary metastasis from the orthotopic site. We demonstrated that enforced expression of exogenous miR-18a, significantly limited continuous growth of primary tumors in mammary gland fat pads and reduced spontaneous lung metastasis. Further investigation on the mechanism of miR-18a action led to the finding that the expression of HIF1A, a key regulator of tumor metastasis, was regulated by miR-18a. Enforced miR-18a expression significantly decreased HIF1A expression at both mRNA and protein levels, resulting in altered transcriptional response and decreased survival of cells in response to Cobalt(II) chloride (CoCl2), a hypoxia-mimicking agent. Conversely, miR-18a knockdown significantly increased HIF1A expression levels and enhanced cell survival in response to CoCl2. Analysis of expression data of human breast tumor tissues showed that miR-18a expression is inversely correlated with HIF1A expression in basal-like breast tumors, supporting a role of miR-18a in restricting HIF1A expression in this subtype of breast cancer. In addition, we demonstrated that hypoxia inhibits miR-18a expression, likely through MYC inactivation. Furthermore, gene expression and functional analysis revealed that miR-18a also plays a role in regulating cell adhesion, migration and invasion. Taken together, this study provides evidence for a novel role of miR-18a to inhibit breast cancer metastasis. Our results suggest that miR-18a downregulation might provide tumor cells survival/growth advantage under hypoxic pressure in basal-like breast cancer. A lung metastatic subline, designated as MB231RN-LM, was derived from MDA-MB-231 breast cancer cells through in vivo selection. The MB231RN-LM cells were stably transfected with has-miR-18a or control vector and treated with 200uM Cobalt(II) chloride (CoCl2, a hypoxia-mimicking agent) for 4 hr. A total of 8 samples were subjected to microarray analysis, with two biological repeats for each experiment condition.

Project description:The Mexican axolotl provides a powerful model to investigate mechanisms of tissue regeneration. A recent chemical screen found that HDAC inhibitor romidepsin, administered for only 1-minute post amputation (1 MPA), blocks axolotl tail regeneration. Here, we tested the potential for cobalt chloride (CoCl2), a chemical stabilizer of HIF1a and inducer of hypoxia, to rescue romidepsin-inhibition of tail regeneration. Tail regeneration was partially rescued when embryos with amputated tails were co-treated with romidepsin and CoCl2. However, extending the CoCl2 dosage window either inhibited regeneration (CoCl2:0-30 MPA) or was lethal (CoCl2:0-24 hours post amputation; HPA). CoCl2:0-30 MPA caused tissue damage, tissue loss, and cell death at the distal tail tip, and blocked regeneration. In contrast, CoCl2 treatment of non-amputated embryos or CoCl2:60-90 MPA treatment of amputated embryos did not affect wound healing or inhibit tail regeneration. To further investigate the contrasting effects of CoCl2, microarray analysis was performed to identify differentially expressed genes at 3 HPA. CoCl2-romidepsin:1 MPA treatment significantly increased the expression of transcription factors associated with appendage regeneration, while CoCl2:0-30 MPA significantly increased expression of hemoglobin and platelet-specific transcripts, consistent with hemorrhage and an impaired hemostatic response. Also, CoCl2:0-30 MPA significantly increased expression of hypoxia inducible genes, including genes that encode Hif1a interacting proteins and heat shock proteins (HSP); in contrast, genes encoding TGFB signaling components were significantly downregulated. Using additional chemical inhibitors of tail regeneration, we identified transcriptional responses associated with HSP90 activity and TGFB signaling. Notably, geldanamcin decreased transcription of matrix metalloproteinases and sustained muscle-specific gene expression, suggesting a role for HSP90 in regulating extracellular matrix remodeling and muscle dedifferentiation. Our study shows the power of using chemical tools to precisely identify temporal windows within which critical biological processes are enacted during tissue regeneration.

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ChIP-seq of H3K27acethylation of human aortic endothelial cells (HAECs) treated with Cobalt chloride (CoCl2)

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