The role of cardiac transcription factor NKX2-5 in regulating the human cardiac miRNAome.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA556644 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9833150.fastq.gz | Fastqsanger.gz | |||
| SRR9833160.fastq.gz | Fastqsanger.gz | |||
| SRR9833151.fastq.gz | Fastqsanger.gz | |||
| SRR9833161.fastq.gz | Fastqsanger.gz | |||
| SRR9833152.fastq.gz | Fastqsanger.gz |
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Project description:Aims: MiRNAs are post-transcriptional regulatory molecules with recognized roles in human heart development and disease. The purpose of this study was to define human miRNA expression profile in cardiac progenitors and early-differentiated cardiomyocytes and to determine if these miRNAs that are governing cardiogenesis is dependent on NKX2-5, a highly conserved pan-cardiac transcription factor. Methods: MiRNA expression profiles of pre-NKX2-5 mesoderm, cardiac progenitors and early cardiomyocytes derived from heterozygous HES3 NKX2-5eGFP/w and null NKX2-5eGFP/eGFP hESC lines were generated by small RNA sequencing in triplicates, using Illumina HiSeq. Reads between 17-28 base pairs were selected for sequence alignment to the human genome (hg19) using Bowtie2. FeatureCounts (Subread, R package) was used to count the number of reads mapping to miRNAs and analysis of statistically differentially expressed miRNA was carried out using Limma (Bioconductor) through the statistical language R. qRT–PCR validation was performed using Taqman MicroRNA Assays. Results: We identified 11 miRNAs that were differentially expressed between pre-NKX2-5 mesoderm and cardiac progenitors, and 112 differentially expressed miRNAs between cardiac progenitors and early cardiomyocytes. Four of which were validated with qRT–PCR, including canonical myogenic miRNAs such as MIR-1-1, -133A1 and 208A that were enriched in both the cardiac progenitor and early cardiomyocyte populations. Strikingly, deletion of NKX2-5 did not result in gross changes in cardiac miRNA profile either at progenitor or cardiomyocyte stage. Instead, non-hierarchical clustering and principal component analysis demonstrated that the different stages of differentiation (day 6 vs day 10) was a larger discriminator between samples than NKX2-5 genotype. Conclusion: Our study demonstrates the application of human embryonic stem cells as an in vitro model to investigate the role of miRNAs in human cardiac development. We conclude that while specific miRNAs have been identified in our study to have a role in the early stages cardiac cell fate specification, the majority of cardiac myogenic miRNA program is regulated separately from the highly conserved NKX2-5 -dependent gene network. This study provides a framework for further investigation of other key transcription factors of cardiac muscle development that might drive cardiomyogenic expression of miRNAs.
2019-11-19 | GSE134852 | GEO
Project description:MicroRNAs (miRNAs) are translational regulatory molecules with recognised roles in heart development and disease. Therefore, it is important to define the human miRNA expression profile in cardiac progenitors and early-differentiated cardiomyocytes and to determine whether critical cardiac transcription factors such as NKX2-5 regulate miRNA expression. We used an NKX2-5eGFP/w reporter line to isolate both cardiac committed mesoderm and cardiomyocytes. We identified 11 miRNAs that were differentially expressed in NKX2-5 -expressing cardiac mesoderm compared to non-cardiac mesoderm. Subsequent profiling revealed that the canonical myogenic miRNAs including MIR1-1, MIR133A1 and MIR208A were enriched in cardiomyocytes. Strikingly, deletion of NKX2-5 did not result in gross changes in the cardiac miRNA profile, either at committed mesoderm or cardiomyocyte stages. Thus, in early human cardiomyocyte commitment and differentiation, the cardiac myogenic miRNA program is predominantly regulated independently of the highly conserved NKX2-5 -dependant gene regulatory network.
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Project description:Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage “super-enhancer” near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
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Project description:Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage “super-enhancer” near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
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Project description:Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage “super-enhancer” near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
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