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Article Summary: RNAseq Techniques Provide Insight into Two Types of Cardiac Hypertrophy


In the study “Deep RNA sequencing reveals novel cardiac transcriptomic signatures for physiological and pathological hypertrophy” Song et al. (2012) cast light on the unique gene expression patterns that characterize two outwardly similar forms of cardiac hypertrophy. Physiological hypertrophy (PHH) is exercise or pregnancy-induced thickening of heart muscles. Pathological hypertrophy (PAH), on the other hand, is a response to disease stressors like high blood pressure or cardiac tissue damage. Song et al. used a mouse model to compare the whole transciptome between PHH and PAH heart muscle cells. Since only PAH leads to fatal heart failure, gene-expression differences revealed those genes and pathways that are unique to disease-causing forms of this condition.

By comparing samples from PAH, PHH, and control mice investigators identified 2,041 differentially expressed genes (DEGs) in PAH, but only 245 in PHH. Furthermore, of the 83 genes that were differentially expressed in both hypertrophy groups, 51 were oppositely regulated in PAH and PHH (Figure 1). These results demonstrate that the two forms of hypertrophy result from very different gene expression patterns, in spite of their morphological similarities.

Song et al.’s analysis of the DEGs showed that most were up-regulated in PAH, whereas most were down-regulated in PHH. Upstream sequencing of PAH up-regulated genes implicated FOXM1 and PU.1 as a key transcription factors in PAH (Figure 2 C and D). Meanwhile, upstream sequencing of the 83 genes that were oppositely regulated in PAH and PHH implicated the MAZ transcription factor in both forms of cardiac hypertrophy. Network analysis of PAH enhanced genes highlighted the importance of cell cycle regulators in PAH (Figure 2 A and B). By contrast, network analysis of oppositely regulated genes showed differential regulation of collagen, chemokine, and actin genes in PAH versus PHH.

Song et al. also detected hundreds of alternative splicing (AS) events in each of the hypertrophy models as compared with controls. Most AS events were associated with domain gain or loss in the protein, but others affected protein localization and activity levels (Table 1). A subset of AS events detected in RNAseq, including one previously undocumented isoform, were confirmed using real-time PCR (Figure 3).

Finally, Song et al. combined the DEG and AS data to determine which KEGG pathways were altered in each type of cardiac hypertrophy (Figure 4). They found that muscle contraction and metabolic pathways were down-regulated in PAH, while immune function and cell cycle pathways were up-regulated. In PHH autoimmune pathways were strongly suppressed and demonstrated frequent alternative splicing. Pathways involves in cardiac disease showed greater expression and alternative slicing in PAH than in PHH.

Another notable conclusion from this study was the clear advantage of using RNAseq techniques over standard microarrays. RNAseq expression profiles were consistent with microarray profiles, but were more accurate and sensitive to gene expression levels. Therefore, RNAseq was able to identify a greater number of differentially expressed genes. Furthermore, RNAseq is inherently better able to detect alternative splicing.

Overall, this paper presents clear evidence that PAH and PHH are distinct conditions at the cellular level, in spite of having similar consequences for heart morphology. Among the authors’ most noteworthy findings is identification of FOXM1 as an important transcription factor in PAH pathogenesis. This information could have implications for medical interventions in PAH. Another strong point of the paper was the critical pathway analysis, which integrated the DEG and AS data in a meaningful way. This analysis provided distinct evidence of contrasts between PAH and PHH in terms of which cellular functions are enhanced, suppressed, and otherwise changed.

Works Cited

Hong Ki Song, Seong-Eui Hong, Taeyong Kim, and Do Han Kim. 2012. Deep RNA sequencing reveals novel cardiac transcriptomic signatures for physiological and pathological hypertrophy. PLoS ONE, 7(4) e35552. doi:10.1371/journal.pone.0035552


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