ABSTRACT
BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) appearing in non-coding genomic regions in CVDs. The SNPs may alter gene expression by modifying transcription factor (TF) binding sites and lead to functional consequences in cardiovascular traits or diseases. To understand the underlying molecular mechanisms, it is crucial to identify which variations are involved and how they affect TF binding. METHODS: The SNEEP (SNP exploration and analysis using epigenomics data) pipeline was used to identify regulatory SNPs, which alter the binding behavior of TFs and link GWAS SNPs to their potential target genes for six CVDs. The human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs), monoculture cardiac organoids (MCOs) and self-organized cardiac organoids (SCOs) were used in the study. Gene expression, cardiomyocyte size and cardiac contractility were assessed. RESULTS: By using our integrative computational pipeline, we identified 1905 regulatory SNPs in CVD GWAS data. These were associated with hundreds of genes, half of them non-coding RNAs (ncRNAs), suggesting novel CVD genes. We experimentally tested 40 CVD-associated non-coding RNAs, among them RP11-98F14.11, RPL23AP92, IGBP1P1, and CTD-2383I20.1, which were upregulated in hiPSC-CMs, MCOs and SCOs under hypoxic conditions. Further experiments showed that IGBP1P1 depletion rescued expression of hypertrophic marker genes, reduced hypoxia-induced cardiomyocyte size and improved hypoxia-reduced cardiac contractility in hiPSC-CMs and MCOs. CONCLUSIONS: IGBP1P1 is a novel ncRNA with key regulatory functions in modulating cardiomyocyte size and cardiac function in our disease models. Our data suggest ncRNA IGBP1P1 as a potential therapeutic target to improve cardiac function in CVDs.
Subject(s)
Cardiovascular Diseases , Polymorphism, Single Nucleotide , Humans , Polymorphism, Single Nucleotide/genetics , Genome-Wide Association Study , Cardiovascular Diseases/genetics , Genomics , GenomeABSTRACT
Understanding the factors that underlie the epigenetic regulation of genes is crucial to understand the gene regulatory machinery as a whole. Several experimental and computational studies examined the relationship between different factors involved. Here we investigate the relationship between transcription factors (TFs) and histone modifications (HMs), based on ChIP-seq data in cell lines. As it was shown that gene regulation by TFs differs depending on the CpG class of a promoter, we study the impact of the CpG content in promoters on the associations between TFs and HMs. We suggest an approach based on sparse linear regression models to infer associations between TFs and HMs with respect to CpG content. A study of the partial correlation of HMs for the two classes of high and low CpG content reveals possible CpG dependence and potential candidates for confounding factors in our models. We show that the models are accurate, inferred associations reflect known biological relationships, and we give new insight into associations with respect to CpG content. Moreover, analysis of a ChIP-seq dataset in HepG2 cells of the HM H3K122ac, an HM about little is known, reveals novel TF associations and supports a previously established link to active transcription.
Subject(s)
CpG Islands/genetics , Histones/metabolism , Transcription Factors/metabolism , Cell Line, Tumor , Chromatin Immunoprecipitation Sequencing , Gene Expression Regulation , Histones/genetics , Humans , Models, Biological , Protein Processing, Post-Translational , Transcription Factors/geneticsABSTRACT
The impact of epigenetics on the differentiation of memory T (Tmem) cells is poorly defined. We generated deep epigenomes comprising genome-wide profiles of DNA methylation, histone modifications, DNA accessibility, and coding and non-coding RNA expression in naive, central-, effector-, and terminally differentiated CD45RA+ CD4+ Tmem cells from blood and CD69+ Tmem cells from bone marrow (BM-Tmem). We observed a progressive and proliferation-associated global loss of DNA methylation in heterochromatic parts of the genome during Tmem cell differentiation. Furthermore, distinct gradually changing signatures in the epigenome and the transcriptome supported a linear model of memory development in circulating T cells, while tissue-resident BM-Tmem branched off with a unique epigenetic profile. Integrative analyses identified candidate master regulators of Tmem cell differentiation, including the transcription factor FOXP1. This study highlights the importance of epigenomic changes for Tmem cell biology and demonstrates the value of epigenetic data for the identification of lineage regulators.
