Nf1 Deficiency Increases Mammary Collagen Deposition and Restricts Adipocyte Differentiation Before Tumor Formation
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ABSTRACT:
PROVIDER: PRJNA966987 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24422420_1.fastq.gz | Fastqsanger.gz | |||
| SRR24422420_2.fastq.gz | Fastqsanger.gz | |||
| SRR24422421_1.fastq.gz | Fastqsanger.gz | |||
| SRR24422421_2.fastq.gz | Fastqsanger.gz | |||
| SRR24422422_1.fastq.gz | Fastqsanger.gz |
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Project description:One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where dysregulation of melanocyte development, proliferation and differentiation is considered to play a key etiopathogenic role. To gain better insight in the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented and hyperpigmented lesional café-au-lait skin. Out of 13,850 unique genes, a total of 137 had a significant twofold or more up- (72) or down-regulated (65) expression in NF1+/- melanocytes compared to NF1+/+ melanocytes (genotype effect). Considering possible intrinsic genetic variation in lesional skin, melanocytes showed a total of 51 genes having a significant twofold or more up- (37) or down-regulated (14) expression when they were cultured from hyperpigmentary café-au-lait skin compared to normally pigmented skin (lesional skin type effect). NF1+/- café-au-lait skin melanocytes showed 468 genes with a significant two-fold or more up- (183) or down-regulated (285) expression going beyond the sum of the separate main effects (interaction). Detailed analysis enabled the identification of several modulated genes in NF1+/- (café-au-lait skin) melanocytes, mainly involved in controlling cell proliferation and cell maintenance, in cell adhesion and, surprisingly, in the immune response. An interesting finding was that a high number of transcription factor genes were differentially modulated, among which a specific subset - important in melanocyte-lineage development - showed downregulation in a transcriptional cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.
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Project description:Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra- and/or intracellular changes. In this study, we observed that one of the ATFs Activating transcription factor 3 (ATF3) is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1ɑ) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. Additionally, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion conducive extracellular matrix (ECM) under hypoxic condition. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. It is interesting to note that ATF3's involvement in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Further, we also show that the demethylated DNA region of intron 9a then becomes accessible to CTCF. Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA PolII pause via CTCF at the intron 9a leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results provide a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can be potentially exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion.
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Project description:Analysis of the effect of NF1 second hit mutation to the reading of the whole human genome by comparing the gene expression profiles of neurofibroma derived Schwann cell cultures representing two different NF1 genotypes (NF1+/- and NF1-/-).
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Project description:Schwann cells and macrophages were dissociated from normal DRGs and 1- and 7-month-old neurofibroma. Schwann cells from neurofibroma have Nf1-/- phenotypes. All macrophages have Nf1+/+ phenotypes. We used microarrays (Affymetrix MoGene 2.0 ST GeneChip) to detect transcriptomal changes between 7-month-old neurofibroma Schwann cells (or macrophages) versus 1-month-old wild-type (or neurofibroma) Schwann cells (or macrophages). Expression data of three sets of cells: (1)Schwann cells and macrophages from 1-month-old wild-type mouse dorsal root ganglia, (2) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 1-month-old neurofibroma, (3) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 7-month-old neurofibroma We chopped mouse DRG/neurofibromas into 1-3 mm^3 pieces and plated them in dissociation medium containing 20mL L-15 (Mediatech), 0.5 mg/mL collagenase type 1 (Worthington; Lakewood, NJ), and 2.5 mg/mL dispase protease type II (Cambrex; East Rutherford, NJ) at 37°C for 4-6 hours with shaking. The dissociation reaction was stopped by adding DMEM +10%FBS. Undigested DRG/tumors were excluded by 100µM cell strainer. Cells were collected by centrifugation. For each microarrays (Schwann cell, macrophage), Affymetrix GeneChip Command Console (v4.0.0) was used to create .chp files. All the probe sets on Affymetrix Mouse Gene 2.0 ST array (Mogene-2_0-st-v1.na33.2.mm10) were summarized by Affymetix Expression Console program using robust multi-chip average (RMA) method . After preprocessing steps, data from two batches were combined and their batch effects were corrected using ComBat method Please note that [1] all MP samples are Nf1+/+ (no mutation on Nf1 gene) and the only difference is their ages (1month, 7month) and [2] the 'nf1' in sample title reperesents "neurofibroma type1 disease", not "Nf1 gene".
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