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. 2024 Sep 27;25(19):10402.
doi: 10.3390/ijms251910402.

Profiling Reduced Expression of Contractile and Mitochondrial mRNAs in the Human Sinoatrial Node vs. Right Atrium and Predicting Their Suppressed Expression by Transcription Factors and/or microRNAs

Weixuan Chen  1 , Abimbola J Aminu  1 , Zeyuan Yin  1 , Irem Karaesmen  1 , Andrew J Atkinson  1 , Marcin Kuniewicz  1   2 , Mateusz Holda  1   3 , Jerzy Walocha  2 , Filip Perde  4 , Peter Molenaar  5 , Halina Dobrzynski  1   2
Affiliations

Profiling Reduced Expression of Contractile and Mitochondrial mRNAs in the Human Sinoatrial Node vs. Right Atrium and Predicting Their Suppressed Expression by Transcription Factors and/or microRNAs

Weixuan Chen et al. Int J Mol Sci. .

Abstract

(1) Background: The sinus node (SN) is the main pacemaker of the heart. It is characterized by pacemaker cells that lack mitochondria and contractile elements. We investigated the possibility that transcription factors (TFs) and microRNAs (miRs) present in the SN can regulate gene expression that affects SN morphology and function. (2) Methods: From human next-generation sequencing data, a list of mRNAs that are expressed at lower levels in the SN compared with the right atrium (RA) was compiled. The mRNAs were then classified into contractile, mitochondrial or glycogen mRNAs using bioinformatic software, RStudio and Ingenuity Pathway Analysis. The mRNAs were combined with TFs and miRs to predict their interactions. (3) Results: From a compilation of the 1357 mRNAs, 280 contractile mRNAs and 198 mitochondrial mRNAs were identified to be expressed at lower levels in the SN compared with RA. TFs and miRs were shown to interact with contractile and mitochondrial function-related mRNAs. (4) Conclusions: In human SN, TFs (MYCN, SOX2, NUPR1 and PRDM16) mainly regulate mitochondrial mRNAs (COX5A, SLC25A11 and NDUFA8), while miRs (miR-153-3p, miR-654-5p, miR-10a-5p and miR-215-5p) mainly regulate contractile mRNAs (RYR2, CAMK2A and PRKAR1A). TF and miR-mRNA interactions provide a further understanding of the complex molecular makeup of the SN and potential therapeutic targets for cardiovascular treatments.

Keywords: Ingenuity Pathway Analysis; contractile function; glycogen metabolism; human right atrium; human sinus node/sinoatrial node; miRNA; mitochondrial function; transcription factor.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(a) Micro-computed tomography (micro-CT) scan of the human SN region (as previously shown and identified by Stephenson et al., 2017 [1]). The white arrow points to the darker region, which is identified as the SN region. (b) Heatmap of the 1357 mRNAs that are expressed at lower levels in the SN than RA. Greener color indicates higher gene expression and redder color indicates lower gene expression. (c) mRNAs relevant to glycogen metabolism with lower gene expression in SN compared to RA. The names of these mRNAs are listed on the Y-axis. The adjusted p values between SN and RA are shown for each mRNA, *** 0.0001 < p ≤ 0.001, **** p < 0.0001.
Figure 2
Figure 2
Gene ontology analysis performed to categorize 1357 mRNAs expressed at lower levels in SN compared to RA. The red arrows point to the categories that are not related to contractile function, mitochondrial function, or glycogen metabolism, and therefore the genes in these categories were deleted from further analysis. (a) Biological process category of the mRNAs. (b) Cellular compartment category of the mRNAs. (c) Molecular function category of the mRNAs.
Figure 3
Figure 3
Ingenuity Pathway Analysis shows the significantly lower-expressed canonical pathways in the SN compared to RA. The numbers on the right of each bar indicate the numbers of genes involved in each canonical pathway. The blue colour represents the negative z-score.
Figure 4
Figure 4
Adjusted p values of significantly more highly expressed transcription factors (a) and miRNAs (b) in SN compared to RA.
Figure 5
Figure 5
Interactions of the higher-expressed TFs and the lower-expressed mRNAs in the SN compared with RA. A summary of the predicted interactions between TFs and mRNAs is listed in Table 3. Blue: mRNAs that are involved with mitochondrial function. Orange: mRNAs that are involved with contractile function. Red: TFs. —: interaction. —|: inhibition.
Figure 6
Figure 6
Interactions of the more highly expressed miRs and lower-expressed mRNAs in SN compared to RA. A summary of the predicted interactions between miRs and mRNAs is listed in Table 4 Blue: mRNAs that are involved in mitochondrial function. Orange: mRNAs that are involved in contractile function. Purple: miRs. →|: inhibition.
Figure 7
Figure 7
mRNAs that have predicted interactions with both TFs and miRs are shown. A summary of the predicted interactions with TFs, miRNAs and mRNAs is listed in Table 2 and Table 3. Blue: mRNAs that are involved with mitochondrial function. Orange: mRNAs that are involved with contractile function. Red: TFs. Purple: miRs. —: interaction. →|: inhibition.
Figure 8
Figure 8
Interactions of mRNAs involved with glycogen metabolism with TFs and miRs. The expression levels of the glycogen metabolic mRNAs are shown in Figure 1c. Red: TFs. Purple: miRs. White: mRNAs that are involved with glycogen metabolism. —: interaction. →|: inhibition.
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