Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database

Abstract

Development of safer drugs based on epigenetic modifiers, e.g., histone deacetylase inhibitors (HDACi), requires better understanding of their effects on cardiac electrophysiology. Using RNAseq data from the genotype-tissue-expression database (GTEx), we created models that link the abundance of acetylation enzymes (HDAC/SIRT/HATs), and the gene expression of ion channels (IC) via select cardiac transcription factors (TFs) in male and female adult human hearts (left ventricle, LV). Gene expression data (transcripts per million, TPM) from GTEx donors (21–70 y.o.) were filtered, normalized and transformed to Euclidian space to allow quantitative comparisons in 84 female and 158 male LVs. Sex-specific partial least-square (PLS) regression models, linking gene expression data for HDAC/SIRT/HATs to TFs and to ICs gene expression, revealed tight co-regulation of cardiac ion channels by HDAC/SIRT/HATs, with stronger clustering in the male LV. Co-regulation of genes encoding excitatory and inhibitory processes in cardiac tissue by the acetylation modifiers may help explain their predominantly net-neutral effects on cardiac electrophysiology. ATP1A1, encoding for the Na/K pump, represented an outlier—with orthogonal regulation by the acetylation modifiers to most of the ICs. The HDAC/SIRT/HAT effects were mediated by strong (+) TF regulators of ICs, e.g., MEF2A and TBX5, in both sexes. Furthermore, for male hearts, PLS models revealed a stronger (+/-) mediatory role on ICs for NKX25 and TGF1B/KLF4, respectively, while RUNX1 exhibited larger (-) TF effects on ICs in females. Male-trained PLS models of HDAC/SIRT/HAT effects on ICs underestimated the effects on some ICs in females. Insights from the GTEx dataset about the co-expression and transcriptional co-regulation of acetylation-modifying enzymes, transcription factors and key cardiac ion channels in a sex-specific manner can help inform safer drug design.

Non Parametric Differential Network Analysis for Biological Data

“…Genotype-Tissue Expression (GTEx) data portal [15], which is a publicly available resource containing expression data of patients integrated with information related to the tissue of provenance, sex and age (grouped into six classes). The current version of the GTEx database accessed on February 01st stores 17382 samples of 54 tissues of 948 donors, see at https://gtexportal.org/home/tissueSummaryPage [17, 20, 19]. We downloaded data and integrated it with information related to sex and age with an ad-hoc realised script.…”

Differential network analysis between sex of thegenes related to comorbidities of type 2 mellitusdiabetes.

“…The current version of the GTEx database accessed on February 01th stores 17382 samples of 54 tissues of 948 donors, see at https://gtexportal.org/home/tissueSummaryPage. It is available thorugh a web interface offering easy and efficient data querying and visualisation [37,10,38,39]. Data may also be downloaded and analysed through an ad hoc realised script.…”

Sex Age Annotated Omics Data: Enabling Powerful Omics Studies

“…GTEx has a web interface which offers query interfaces and visualisation. In recent years many independent studies used GTEx data to perform ageing-based analysis [18,[28][29][30].…”