Dataset Information

In vivo role of different domains and of phosphorylation in the transcription factor Nkx2-1.

ABSTRACT: The transcription factor Nkx2-1 (also known as TTF-1, Titf1 or T/EBP) contains two apparently redundant activation domains and is post-translationally modified by phosphorylation. We have generated mouse mutant strains to assess the roles of the two activation domains and of phosphorylation in mouse development and differentiation.Mouse strains expressing variants of the transcription factor Nkx2-1 deleted of either activation domain have been constructed. Phenotypic analysis shows for each mutant a distinct set of defects demonstrating that distinct portions of the protein endow diverse developmental functions of Nkx2-1. Furthermore, a mouse strain expressing a Nkx2-1 protein mutated in the phosphorylation sites shows a thyroid gland with deranged follicular organization and gene expression profile demonstrating the functional role of phosphorylation in Nkx2-1.The pleiotropic functions of Nkx2-1 are not all due to the protein as a whole since some of them can be assigned to separate domains of the protein or to specific post-translational modifications. These results have implication for the evolutionary role of mutations in transcription factors.

SUBMITTER: Silberschmidt D

PROVIDER: S-EPMC3055846 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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In vivo role of different domains and of phosphorylation in the transcription factor Nkx2-1.

Silberschmidt Daniel D Rodriguez-Mallon Alina A Mithboakar Prathiba P Calì Gaetano G Amendola Elena E Sanges Remo R Zannini Mariastella M Scarfò Marzia M De Luca Pasquale P Nitsch Lucio L Di Lauro Roberto R De Felice Mario M

BMC developmental biology 20110223

<h4>Background</h4>The transcription factor Nkx2-1 (also known as TTF-1, Titf1 or T/EBP) contains two apparently redundant activation domains and is post-translationally modified by phosphorylation. We have generated mouse mutant strains to assess the roles of the two activation domains and of phosphorylation in mouse development and differentiation.<h4>Results</h4>Mouse strains expressing variants of the transcription factor Nkx2-1 deleted of either activation domain have been constructed. Phen ...[more]

PMID: 21345181

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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.

Dataset Information

In vivo role of different domains and of phosphorylation in the transcription factor Nkx2-1.

Publications

In vivo role of different domains and of phosphorylation in the transcription factor Nkx2-1.

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