Abstract
BackgroundCell-type-specific genes exhibit heterogeneity in genomic contexts and may be subject to different epigenetic regulations through different gene transcriptional processes depending on the cell type involved. The gene-body regions (GBRs) of some cardiomyocyte (CM)-specific genes are long and highly hypomethylated in CMs. To explore the cell-type specificities of epigenetic patterns and functions, multiple epigenetic modifications of GBRs were compared among CMs, liver cells and embryonic stem cells (ESCs).ResultsWe found that most genes show a moderately negative correlation between transcript levels and gene lengths. As CM-specific genes are generally longer than other cell-type-specific genes, we hypothesized that the gene-body epigenetic features of CMs may support the transcriptional regulation of CM-specific genes. We found gene-body DNA hypomethylation in a CM-specific gene subset co-localized with rare gene-body marks, including RNA polymerase II (Pol II) and p300. Interestingly, 5-hydroxymethylcytosine (5hmC) within the gene body marked cell-type-specific genes at neonatal stages and active gene-body histone mark H3K36 trimethylation declined and overlapped with cell-type-specific gene-body DNA hypomethylation and selective Pol II/p300 accumulation in adulthood. Different combinations of gene-body epigenetic modifications were also observed with genome-wide scale cell-type specificity, revealing the occurrence of dynamic epigenetic rearrangements in GBRs across different cell types.ConclusionsAs 5hmC enrichment proceeded to hypomethylated GBRs, we considered that hypomethylation may not represent a static state but rather an equilibrium state of turnover due to the balance between local methylation linked to transcription and Tet oxidative modification causing demethylation. Accordingly, we conclude that demethylation in CMs can be a used to establish such cell-type-specific epigenetic domains in relation to liver cells. The establishment of cell-type-specific epigenetic control may also change genomic contexts of evolution and may contribute to the development of cell-type-specific transcriptional coordination.
Highlights
Cell-type-specific genes exhibit heterogeneity in genomic contexts and may be subject to different epigenetic regulations through different gene transcriptional processes depending on the cell type involved
As 5hmC enrichment proceeded to hypomethylated Gene body regions (GBR), we considered that hypomethylation may not represent a static state but rather an equilibrium state of turnover due to the balance between local methylation linked to transcription and Tet oxidative modification causing demethylation
Two groups of genes exhibited CM-specific expression patterns and presented different expression levels in CMs, while another two groups exhibited embryonic stem cells (ESCs)-specific expression patterns. Another group contained liverspecific genes, and one contained genes commonly expressed in both CMs and liver cells; the remaining six groups contained constitutively expressed genes identified in the three cell types with different expression levels (Fig. 1b, Additional file 1: Figure S1)
Summary
Cell-type-specific genes exhibit heterogeneity in genomic contexts and may be subject to different epigenetic regulations through different gene transcriptional processes depending on the cell type involved. At least one-third of the total length of the genome is transcribed as the pre-mRNA of coding genes, and individual gene-body lengths are highly heterogeneous and can contain a few hundred to a million base pairs. Such variations in genomic size are mostly attributed to the presence of intronic and repetitive sequences [1], differences between different organisms and even between eutherians and metatherians [2]. In addition to structural protein genes, the gene encoding transcription factor Mef2c is long (163 kb) Such long gene lengths may be disadvantageous during transcription because they require that transcriptional elongation be maintained over long distances without interruption. These long gene sequences are expressed at high levels in CMs in the same nuclear environment where housekeeping (HK) genes are highly and constitutively transcribed; cell-type-specific epigenetic features that overcome the disadvantages of such long genes must be present
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