Abstract
Transcription factors organize gene expression profiles by regulating promoter activity. However, the role of transcription factors after transcription initiation is poorly understood. Here, we show that the homeoprotein Nkx2-5 and the 5'-3' exonuclease Xrn2 are involved in the regulation of alternative polyadenylation (APA) during mouse heart development. Nkx2-5 occupied not only the transcription start sites (TSSs) but also the downstream regions of genes, serving to connect these regions in primary embryonic cardiomyocytes (eCMs). Nkx2-5 deficiency affected Xrn2 binding to target loci and resulted in increases in RNA polymerase II (RNAPII) occupancy and in the expression of mRNAs with long 3'untranslated regions (3' UTRs) from genes related to heart development. siRNA-mediated suppression of Nkx2-5 and Xrn2 led to heart looping anomaly. Moreover, Nkx2-5 genetically interacts with Xrn2 because Nkx2-5(+/-)Xrn2(+/-), but neither Nkx2-5(+/-)nor Xrn2(+/-), newborns exhibited a defect in ventricular septum formation, suggesting that the association between Nkx2-5 and Xrn2 is essential for heart development. Our results indicate that Nkx2-5 regulates not only the initiation but also the usage of poly(A) sites during heart development. Our findings suggest that tissue-specific transcription factors is involved in the regulation of APA.
Highlights
Transcription factors and chromatin regulators orchestrate the processes of heart development by positively and negatively regulating thousands of genes (Bruneau, 2010; Nimura et al, 2009; Prall et al, 2007; Srivastava, 2006; Takeuchi and Bruneau, 2009; Takeuchi et al, 2011)
We examined whether the occupancy of Nkx2-5 and Tbx5 is correlated with gene expression levels because these two transcription factors are associated with RNA polymerase II (RNAPII)
The importance of cardiac transcription factors had been shown in many reports; for example, mutations in transcription factors, such as Nkx2-5, caused defects in heart development (Bruneau, 2008; Srivastava, 2006)
Summary
Transcription factors and chromatin regulators orchestrate the processes of heart development by positively and negatively regulating thousands of genes (Bruneau, 2010; Nimura et al, 2009; Prall et al, 2007; Srivastava, 2006; Takeuchi and Bruneau, 2009; Takeuchi et al, 2011). Nimura et al have studied mice to investigate the role of a transcription factor called Nkx, which was known to be important for heart development This revealed that in addition to its expected role in starting the transcription of genes that are important for heart development, Nkx controls the length of 3’ untranslated regions of certain mRNAs. To do so, Nkx binds to a protein called Xrn that stops transcription when the end of the gene is reached. Our findings suggest that Nkx is involved in the regulation of the length of the 3’ UTR and may help to elucidate the mechanisms by which transcription factor deficiencies can cause diseases such as CHD
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