Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

MCasz1_conditional knockout

ABSTRACT: The overall goal of our studies is to elucidate the cellular and molecular mechanism by which the transcription factor Casz1 functions in murine heart development. We established that Casz1 is expressed in myocardial progenitor cells beginning at E7.5 and in differentiated cardiomyocytes throughout development. We generated conditional Casz1 knockout mice to show that ablation of CASZ1 in Nkx2.5-positive cardiomyocytes leads to cardiac hypoplasia, ventricular septal defects and lethality by E13.5. To identify the pathways and networks by which Casz1 regulates cardiomyocyte development, we used RNA-Seq and identified genes involved in cell proliferation are upregulated in Casz1 mutants compared to wild-type littermates. We conclude that Casz1 is essential for cardiac development and has a pivotal role in regulating part of the cardiac transcriptional program. 3 biological replicates of the two genotypes (Nkx2-5+/+,Casz1f/+ and Nkx2-5Cre/+,Casz1f/f) were used for RNA-seq to determine genes that are differentially expressed in the murine heart when Casz1 is mutated. Nkx2-5+/+,Casz1f/+ were used as wild-type controls for comparison.

ORGANISM(S): Mus musculus

SUBMITTER: Nirav Amin

PROVIDER: E-GEOD-55394 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development.

Dorr Kerry M KM Amin Nirav M NM Kuchenbrod Lauren M LM Labiner Hanna H Charpentier Marta S MS Pevny Larysa H LH Wessels Andy A Conlon Frank L FL

Development (Cambridge, England) 20150507 11

Organ growth occurs through the integration of external growth signals during the G1 phase of the cell cycle to initiate DNA replication. Although numerous growth factor signals have been shown to be required for the proliferation of cardiomyocytes, genetic studies have only identified a very limited number of transcription factors that act to regulate the entry of cardiomyocytes into S phase. Here, we report that the cardiac para-zinc-finger protein CASZ1 is expressed in murine cardiomyocytes. ...[more]

PMID: 25953344

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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

MCasz1_conditional knockout

Publications

Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development.

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