Next Generation Sequencing Analysis of Wild Type and Hypomorphic Nkx2-5 mutant heart Transcriptomes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE44573 | GEO | 2015/09/02
SECONDARY ACCESSION(S): PRJNA190089
REPOSITORIES: GEO
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Project description:We report the transcriptome analysis of E11.5 mouse embryonic heart presenting a reduction in Nkx2-5 expression compare to wild-type littermate. Transcriptome analysis of 3 different E11.5 hypomorphic hearts against 3 controls littermate hearts.
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Project description:Cell-specific gene expression is achieved by a combination of mechanisms including transcriptional and post-transcriptional regulation. The transcription factor Nkx2-1, essential for lung cell differentiation, mainly acts in transcriptional activation but can directly or indirectly repress gene expression. microRNAs are a class of small non-coding RNA that control one of the major mechanisms of gene repression. To identify miRNAs regulated by Nkx2-1 that may mediate its repressing effects, we knocked-down Nkx2-1 in mouse lung epithelial cell lines and systematically identified targets by genome-wide miR and mRNA expression analyses. Nkx2-1 controls expression of miRs known to contribute to lung cell differentiation in development and disease and others not previously described. Amongst the significantly altered miRs, the mir-106a-363 cluster, miR-1195, miR-378, and miR-346 are directly correlated with the levels of Nkx2-1, whereas miR-200c/b, miR-221, and miR- 222 are inversely correlated. These miRNAs are expressed in embryonic lung at day E11.5, and/or E19.5 determined by in-situ hybridization. Expression of predicted targets of mir-1195, mir-346 and miR-200c and mir-221/222 were evaluated by mRNA expression microarrays in Nkx2-1 knockdown cells identifying those anti-correlated to the corresponding miRNA expression. Genes regulated by mir-1195, Cyp2s1 and Map3k2, by mir-346, Klf6, and miR-200c, Myb, Nfib, and Six1, were validated by qRT-PCR. Inhibition of mir-1195 confirms the inverse correlation of this miRNA with its putative targets Cyp2s1 and Map3k2. This miRNA-mRNA expression analysis identifies potential paths of Nkx2-1 mediated gene repression, and contributes to the understanding of gene regulation in lung epithelial differentiation and development. Nkx2-1 mRNA was knocked down in lung epithelial cells using a lentivirus expressing a shRNA targeting Nkx2-1 (n=3) and compared to empty vector controls (n=3).
2015-12-22 | E-GEOD-47054 | biostudies-arrayexpress
Project description:Cell-specific gene expression is achieved by a combination of mechanisms including transcriptional and post-transcriptional regulation. The transcription factor Nkx2-1, essential for lung cell differentiation, mainly acts in transcriptional activation but can directly or indirectly repress gene expression. microRNAs are a class of small non-coding RNA that control one of the major mechanisms of gene repression. To identify miRNAs regulated by Nkx2-1 that may mediate its repressing effects, we knocked-down Nkx2-1 in mouse lung epithelial cell lines and systematically identified targets by genome-wide miR and mRNA expression analyses. Nkx2-1 controls expression of miRs known to contribute to lung cell differentiation in development and disease and others not previously described. Amongst the significantly altered miRs, the mir-106a-363 cluster, miR-1195, miR-378, and miR-346 are directly correlated with the levels of Nkx2-1, whereas miR-200c/b, miR-221, and miR- 222 are inversely correlated. These miRNAs are expressed in embryonic lung at day E11.5, and/or E19.5 determined by in-situ hybridization. Expression of predicted targets of mir-1195, mir-346 and miR-200c and mir-221/222 were evaluated by mRNA expression microarrays in Nkx2-1 knockdown cells identifying those anti-correlated to the corresponding miRNA expression. Genes regulated by mir-1195, Cyp2s1 and Map3k2, by mir-346, Klf6, and miR-200c, Myb, Nfib, and Six1, were validated by qRT-PCR. Inhibition of mir-1195 confirms the inverse correlation of this miRNA with its putative targets Cyp2s1 and Map3k2. This miRNA-mRNA expression analysis identifies potential paths of Nkx2-1 mediated gene repression, and contributes to the understanding of gene regulation in lung epithelial differentiation and development. Nkx2-1 mRNA was knocked down in lung epithelial cells using a lentivirus expressing a shRNA targeting Nkx2-1 (n=3) and compared to empty vector controls (n=3).
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Project description:NKX2-5 is a homeodomain transcription factor that plays a central role in the cardiac gene regulatory network, and is commonly mutated in human congenital heart disease. Here, we take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for both wild type NKX2-5 and a mutation lacking the homeodomain (NKX2-5delHD), the latter to model loss-of-function in gene regulatory network. NKX2-5delHD bound hundreds of targets including NKX2-5 wild type targets and a unique set of “off-targets”, and retained partial functionality. We showed that NKX2-5delHD could heterodimerize with NKX2-5 wild type and cofactors, including ubiquitous ETS family members ELK1 and ELK4, through a tyrosine-rich homophilic interaction domain (YRD). NKX2-5delHD off-targets, but not those of an NKX2-5 YRD mutant, were enriched in ETS motifs and were occupied by ELK1/ELK4 proteins, as determined by DamID. Our study reveals unexpected activities for NKX2-5 mutations on chromatin, guided by interactions with their normal cardiac and general cofactors, and suggest potential for a novel type of gain-of-function in congenital heart disease. The supplementary bed file contains all binding regions detected for the N/C-terminal fusions reported in the manuscript, in addition to probe locations, ready to upload directly into UCSC browser (mm9).
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Project description:The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To better understand how genomic alterations of NKX2-1 drive tumorigenesis, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma, and analyzed DNA binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation from NKX2-1-amplified human lung adenocarcinoma cell lines. Combining these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1, in addition to consensus binding motifs including a nuclear hormone receptor signature and a Forkhead box motif in NKX2-1-bound sequences. RNA interference analysis of NKX2-1-amplified cells compared to non-amplified cells demonstrated that LMO3 mediates cell proliferation downstream of NKX2-1; cistromic analysis that NKX2-1 may cooperate with FOXA1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transducer of lineage specific cell survival of NKX2-1-amplified lung adenocarcinomas. NKX2-1 ChIP-seq from three lung adenocarcinoma cell lines with amplification of NKX2-1
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