Unknown,Transcriptomics,Genomics,Proteomics

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Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung

ABSTRACT: Gene expression (RNA-seq) and H3K27me3 binding (ChIP-seq) profiling of wild type and Ezh2-deficient mouse lung epithelium. Lungs from wild type and Ezh2-deficient mice (Ezh2 deletion is specific to lung epithelium) were collected at day e16.5. Lung cells were separated into epithelial and stromal populations based on EpCAM expression. Epithelial cells were profiled for both gene expression (Total RNA-seq) and H3K27me3 binding (ChIP-seq). Additionally, stromal cells were also profiled for gene expression.

ORGANISM(S): Mus musculus

SUBMITTER: Marie-Liesse Asselin-Labat

PROVIDER: E-GEOD-57393 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung.

Galvis Laura A LA Holik Aliaksei Z AZ Short Kieran M KM Pasquet Julie J Lun Aaron T L AT Blewitt Marnie E ME Smyth Ian M IM Ritchie Matthew E ME Asselin-Labat Marie-Liesse ML

Development (Cambridge, England) 20150319 8

Epigenetic mechanisms involved in the establishment of lung epithelial cell lineage identities during development are largely unknown. Here, we explored the role of the histone methyltransferase Ezh2 during lung lineage determination. Loss of Ezh2 in the lung epithelium leads to defective lung formation and perinatal mortality. We show that Ezh2 is crucial for airway lineage specification and alveolarization. Using optical projection tomography imaging, we found that branching morphogenesis is a ...[more]

PMID: 25790853

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Project description:The model describing that aberrant CpG island (CGI) methylation leads to transcription repression of tumor suppressor genes and thereby is implicated in tumor progression has been established in many cancers. However, recent studies indicated aberrantly hypermethylated genes in multiple cancers are already repressed in pre-cancerous tissues despite their promoters are hypomethylated. Here, we hypothesized that the occurrence of CGI promoter hypermethylation in cancers are associated with Polycomb-repressive complex and the associated H3K27me3 mark in pre-cancerous tissues. By using a ChIP-BS-seq technology that examines methylation of the DNA fragments precipitated by the antibodies to histone modifications, we provided direct evidences showing that genes highly enriched with H3K27me3 marks both in cancer and normal cells became aberrantly hypermethylated in CGI promoters in cancer cells in comparison with normal cells. Furthermore, we confirmed that these genes consistently were significantly hypermethylated in TCGA primary cancer in comparison with normal tissues. Thus, we provided direct evidences supporting that the presence of H3K27m3 may serve as a guide to promoter hypermethylation. This will spur future work on epigenetic signature of combined histone and DNA methylation that could define a cancerM-bM-^@M-^Ys epigenetic abnormalities, therefore helping distinguish subtypes of cancers and aiding future diagnosis and therapeutics of cancers. We applied ChIP-BS technology to examine H3K27me3 marks, which are catalyzed by the SET domain histone methyltransferase EZH2 and have a repressive function with 50bp pair-end sequencing. found H3K27me3 marks were enriched preferentially at CpG islands, (+/-500) transcription start sites (TSSs) and exons in two GC cell lines (BGC-823 and AGS). In YH cells, H3K27me3 marks were only preferentially enriched at CpG islands. In contrast, Hela cells presented a reverse pattern with highest H3K27me3 enrichment in intergenic regions. To confirm this result in Hela cells, we performed two independent replicates of ChIP-Seq and ChIP-BS-seq. Cause of useful was relative small. we still sequenced one 100bp pe reads replicate for H3K4me3 and two replicate for H3K27me3 ChIP-BS-seq.

Project description:Nkx2.1 is a critical regulator of mammalian lung development. It is expressed in epithelial cells at the initiation of lung organogenesis, becoming progressively restricted during development to bronchiolar and alveolar type II epithelial cells. In humans, it is a common marker of carcinomas of lung and thyroid origin and is highly amplified in 10-15% of lung adenocarcinomas. Despite its key role in development and disease only a few genes directly regulated by Nkx2.1 are known. To identify direct Nkx2.1target genes and pathways controlled by this transcription factor in vivo we analyzed, by chromatin immuno-precipitation (chip)-on-chip method, Nkx2.1 binding to DNA cis-elements in developing mouse lung. We analyzed embryonic day E11.5 lungs, when Nkx2.1 expressing cells are undergoing predominantly proliferation, and day E19.5, when Nkx2.1 expressing cells are undergoing predominantly differentiation. Many highly bound targets are known and well described, such as surfactant proteins and secretoglobins. Unique or common target genes involved in a variety of developmental and tumorigenic pathways were identified at each developmental time point. Positive regulation of cell proliferation was the highest overrepresented biological process at E11.5 while ion transport was the highest overrepresented biological process at E19.5. New identified targets include proliferation related genes such as E2F3, Met, Ccnb1, and Ccnb2. Nkx2.1 downregulation in mouse epithelial and human carcinoma cell lines reduced cell proliferation by arresting cells in the G2/M phase. Reduced expression of Nkx2.1 target genes in both cell lines supports a direct role of Nkx2.1 in regulation of cell proliferation genes. The identification of these transcriptional regulatory pathways in vivo aid us to understand Nkx2.1 function in lung development and link it to disease, since many of the identified targets are aberrantly up regulated in cancer cells. Developing mouse lung, 2 developmental time points E11.5 and E19.5, genomic DNA fragments immunoprecipitated with a-Nkx2.1 (07-601, Upstate-Millipore) vs input, E11.5, 2 biological replicates and E19.5, 3 biological replicates

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Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung

Publications

Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung.

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