Cargando…

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

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. DNM...

Descripción completa

Detalles Bibliográficos
Autores principales: Emon, Isaac M., Al-Qazazi, Ruaa, Rauh, Michael J., Archer, Stephen L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10650407/
https://www.ncbi.nlm.nih.gov/pubmed/37947606
http://dx.doi.org/10.3390/cells12212528
_version_ 1785135773862854656
author Emon, Isaac M.
Al-Qazazi, Ruaa
Rauh, Michael J.
Archer, Stephen L.
author_facet Emon, Isaac M.
Al-Qazazi, Ruaa
Rauh, Michael J.
Archer, Stephen L.
author_sort Emon, Isaac M.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10650407
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-106504072023-10-26 The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases Emon, Isaac M. Al-Qazazi, Ruaa Rauh, Michael J. Archer, Stephen L. Cells Review 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. MDPI 2023-10-26 /pmc/articles/PMC10650407/ /pubmed/37947606 http://dx.doi.org/10.3390/cells12212528 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Emon, Isaac M.
Al-Qazazi, Ruaa
Rauh, Michael J.
Archer, Stephen L.
The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases
title The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases
title_full The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases
title_fullStr The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases
title_full_unstemmed The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases
title_short The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases
title_sort role of clonal hematopoiesis of indeterminant potential and dna (cytosine-5)-methyltransferase dysregulation in pulmonary arterial hypertension and other cardiovascular diseases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10650407/
https://www.ncbi.nlm.nih.gov/pubmed/37947606
http://dx.doi.org/10.3390/cells12212528
work_keys_str_mv AT emonisaacm theroleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases
AT alqazaziruaa theroleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases
AT rauhmichaelj theroleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases
AT archerstephenl theroleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases
AT emonisaacm roleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases
AT alqazaziruaa roleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases
AT rauhmichaelj roleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases
AT archerstephenl roleofclonalhematopoiesisofindeterminantpotentialanddnacytosine5methyltransferasedysregulationinpulmonaryarterialhypertensionandothercardiovasculardiseases