The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases

Cells. 2023 Oct 26;12(21):2528. doi: 10.3390/cells12212528.

Abstract

DNA methylation is an epigenetic mechanism that regulates gene expression without altering gene sequences in health and disease. DNA methyltransferases (DNMTs) are enzymes responsible for DNA methylation, and their dysregulation is both a pathogenic mechanism of disease and a therapeutic target. DNMTs change gene expression by methylating CpG islands within exonic and intergenic DNA regions, which typically reduces gene transcription. Initially, mutations in the DNMT genes and pathologic DNMT protein expression were found to cause hematologic diseases, like myeloproliferative disease and acute myeloid leukemia, but recently they have been shown to promote cardiovascular diseases, including coronary artery disease and pulmonary hypertension. We reviewed the regulation and functions of DNMTs, with an emphasis on somatic mutations in DNMT3A, a common cause of clonal hematopoiesis of indeterminant potential (CHIP) that may also be involved in the development of pulmonary arterial hypertension (PAH). Accumulation of somatic mutations in DNMT3A and other CHIP genes in hematopoietic cells and cardiovascular tissues creates an inflammatory environment that promotes cardiopulmonary diseases, even in the absence of hematologic disease. This review summarized the current understanding of the roles of DNMTs in maintenance and de novo methylation that contribute to the pathogenesis of cardiovascular diseases, including PAH.

Keywords: DNA methylation; Tatton-Brown-Rahman Syndrome; congenital heart disease; diabetes; epigenetic regulation; group 1 pulmonary hypertension; inflammation.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiovascular Diseases* / genetics
  • Clonal Hematopoiesis
  • DNA
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methyltransferase 3A
  • DNA, Intergenic
  • Humans
  • Methyltransferases / genetics
  • Pulmonary Arterial Hypertension* / genetics

Substances

  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • Methyltransferases
  • DNA
  • DNA, Intergenic

Grants and funding

We thank the Canadian Institutes of Health Research (CIHR) (Grants 437492 & 333058), the William James Henderson Foundation, the Canadian Foundation for Innovation (33518), the Translational Institute of Medicine (TIME), and the QCPU for their continued support.