Comparative Study of Transcriptome in the Hearts Isolated from Mice, Rats, and Humans

Abstract

The heart is a significant organ in mammalian life, and the heartbeat mechanism has been an essential focus of science. However, few studies have focused on species differences. Accordingly, challenges remain in studying genes that have universal functions across species and genes that determine species differences. Here, we analyzed transcriptome data in mouse, rat, and human atria, ventricles, and sinoatrial nodes (SA) obtained from different platforms and compared them by calculating specificity measure (SPM) values in consideration of species differences. Among the three heart regions, the species differences in SA were the greatest, and we searched for genes that determined the essential characteristics of SA, which was SHOX2 in our criteria. The SPM value of SHOX2 was prominently high across species. Similarly, by calculating SPM values, we identified 3 atrial-specific, 11 ventricular-specific, and 17 SA-specific markers. Ontology analysis identified 70 cardiac region- and species-specific ontologies. These results suggest that reanalyzing existing data by calculating SPM values may identify novel tissue-specific genes and species-dependent gene expression. This study identified the importance of SHOX2 as an SA-specific transcription factor, a novel cardiac regional marker, and species-dependent ontologies.

Local tissue mechanics control cardiac pacemaker cell embryonic patterning

“…After functional validation, we confirmed consistency in our RNA sequencing across sample pools by conducting principal component analysis and examining the expression of known positive (Shox2, Isl1, Tbx3, Hcn4, Flrt3, Lsps1) and negative (Nkx2.5, Scn5a, Bmp10, Gja5) markers of CPCs (Hoogaars et al, 2004(Hoogaars et al, , 2007Blaschke et al, 2007;Espinoza-Lewis et al, 2009;Wiese et al, 2009;Bakker et al, 2012;Ye et al, 2015aYe et al, , 2015bIonta et al, 2015;Liang et al, 2015Liang et al, , 2020Bressan et al, 2018;Li et al, 2019;van Eif et al, 2019;Thomas et al, 2021;Okada et al, 2022). Marker gene expression analysis indicated that all three sample pools showed similar fold differences in previously identified differentially expressed genes (Fig S1B ) and principal component analysis demonstrated strong separation between SAN and atrial sample pools (Fig S1C).…”

“…Indeed, the atypical microarchitecture present in the SAN has garnered significant interest over the last 100 years ( Opthof, 1988 ; Shiraishi et al, 1992 ; Csepe et al, 2015, 2016 ; Ho & Sá nchez-Quintana, 2016 ; Kalyanasundaram et al, 2019 ). State-of-the-art transcriptional and proteomic profiling have begun to reveal the diversity and specialization of the ECM present in the mature SAN ( Liang et al, 2015 ; Vedantham et al, 2015 ; Gluck et al, 2017 ; Li et al, 2019 ; Linscheid et al, 2019 ; van Eif et al, 2019 ; Brennan et al, 2020 ; Kalyanasundaram et al, 2021 ; Mandla et al, 2021 ; Minhas et al, 2021 ; Okada et al, 2022 ) which has given rise to the hypothesis that the mechanical properties of the SAN microenvironment may be important for overall CPC function ( Gluck et al, 2017 ; Linscheid et al, 2019 ; Kalyanasundaram et al, 2021 ). However, this model has not been empirically tested and few data are available to assess how local biomechanics influence CPC activity.…”

Mathematical model for the relationship between single-cell and bulk gene expression to clarify the interpretation of bulk gene expression data

“…In DE analysis, if gene expression levels differ significantly between diseased and non-diseased donors, then the genes are considered to be associated with that disease. Similarly, a comparison of gene expression data from different tissues or anatomical regions can therefore be used to identify tissue/region-specific genes [5] , [6] , [7] . Expression quantitative trait locus analysis (eQTL) can be used to identify genetic variants in genotype groups that are significantly associated with gene expression levels, and in so doing, can facilitate an understanding of the mechanisms underlying gene regulation and interpretations of functional genetic variants [8] , [9] .…”

Molecular Pathogenesis of Cardiac Arrhythmia

“…On the other hand, to elucidate the mechanism of cardiac function, Dr. Namekata et al and Dr. Okada et al employed a strategy of comparing different animal species [ 4 , 5 ]. To our knowledge, the normal beating heart is driven by a coupled-clock system in which Ca 2+ release preceding the action potential is reflected in depolarization via a Na + –Ca 2+ exchanger (NCX).…”

“…Similarly, Dr. Okada et al dismissed the high-scoring report stating that Tbx18 is the most critical transcription factor that characterizes pacemaker cells [ 8 ]. They reported that SHOX2 is the essential transcription factor for pacemaker cells when animal species, including humans, are considered [ 5 ].…”