Cell-Specific PEAR1 Methylation Studies Reveal a Locus that Coordinates Expression of Multiple Genes

Abstract

Chromosomal interactions connect distant enhancers and promoters on the same chromosome, activating or repressing gene expression. PEAR1 encodes the Platelet-Endothelial Aggregation Receptor 1, a contact receptor involved in platelet function and megakaryocyte and endothelial cell proliferation. PEAR1 expression during megakaryocyte differentiation is controlled by DNA methylation at its first CpG island. We identified a PEAR1 cell-specific methylation sensitive region in endothelial cells and megakaryocytes that showed strong chromosomal interactions with ISGL20L2, RRNAD1, MRLP24, HDGF and PRCC, using available promoter capture Hi-C datasets. These genes are involved in ribosome processing, protein synthesis, cell cycle and cell proliferation. We next studied the methylation and expression profile of these five genes in Human Umbilical Vein Endothelial Cells (HUVECs) and megakaryocyte precursors. While cell-specific PEAR1 methylation corresponded to variability in expression for four out of five genes, no methylation change was observed in their promoter regions across cell types. Our data suggest that PEAR1 cell-type specific methylation changes may control long distance interactions with other genes. Further studies are needed to show whether such interaction data might be relevant for the genome-wide association data that showed a role for non-coding PEAR1 variants in the same region and platelet function, platelet count and cardiovascular risk.

Genome sequencing unveils a regulatory landscape of platelet reactivity

“…The minor allele of rs12041331 is linked to decreased PEAR1 platelet protein levels 14,15 , potentially through alteration of a methylation site in MKs 22 . In addition, the role of this gene in platelet signaling is supported by mechanistic studies 23,24 . Here, a sequencingbased approach followed by co-localization with platelet eQTLs reveal that results are consistent with a model that a single, common causal variant explains the platelet reactivity signal with respect to PEAR1.…”

PEAR1 Genetic Variants in Essential Thrombocythemia: A New Study of The Prevalence and Association of PEAR1 Variants with Hematological Parameters and ET Mutations

“…Genetic researchers have discovered that more than 15% of platelet dysfunction cases are related to rs12041331variant. Other studies have also revealed that rs12041331 and rs12566888 variants account for over 1% of platelet phenotypic variation (15,38,39). These two PEAR1 variants (rs12041331 and rs12566888) are located far from each other in the PEAR1 gene, but the GG allele in rs12041331 is closely related to the TT allele in rs12566888 and change the platelet activity with a similar mechanism (16, 40).…”

Association of colorectal cancer with genetic and epigenetic variation in PEAR1—A population-based cohort study

“…The interaction with platelets facilitates cancer cells to escape from immune recognition [ 8 , 9 ]. Our recent experimental data also showed that, via the methylation of its promoter, PEAR1 mediates chromosome interactions with other genes, such as PRCC and HDGF , which are both involved in cell proliferation [ 29 ]. These observations highlight the potential involvement of genetic variation in PEAR1 in modulating the risk of colorectal cancer.…”