Michelle Lacey1, Carl Baribault2, Kenneth C Ehrlich3, Melanie Ehrlich4. 1. Tulane Cancer Center, Tulane University Health Sciences Center, LA, 70112, USA; Department of Mathematics, Tulane University, New Orleans, LA, 70118, USA. 2. Tulane Cancer Center, Tulane University Health Sciences Center, LA, 70112, USA. 3. Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, USA. 4. Tulane Cancer Center, Tulane University Health Sciences Center, LA, 70112, USA; Center for Bioinformatics and Genomics, Tulane University Health Sciences Center, USA; Hayward Genetics Center, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA. Electronic address: ehrlich@tulane.edu.
Abstract
BACKGROUND AND AIMS: Atherosclerosis is a widespread and complicated disease involving phenotypic modulation and transdifferentiation of vascular smooth muscle cells (SMCs), the predominant cells in aorta, as well as changes in endothelial cells and infiltrating monocytes. Alterations in DNA methylation are likely to play central roles in these phenotypic changes, just as they do in normal differentiation and cancer. METHODS: We examined genome-wide DNA methylation changes in atherosclerotic aorta using more stringent criteria for differentially methylated regions (DMRs) than in previous studies and compared these DMRs to tissue-specific epigenetic features. RESULTS: We found that disease-linked hypermethylated DMRs account for 85% of the total atherosclerosis-associated DMRs and often overlap aorta-associated enhancer chromatin. These hypermethylated DMRs were associated with functionally different sets of genes compared to atherosclerosis-linked hypomethylated DMRs. The extent and nature of the DMRs could not be explained as direct effects of monocyte/macrophage infiltration. Among the known atherosclerosis- and contractile SMC-related genes that exhibited hypermethylated DMRs at aorta enhancer chromatin were ACTA2 (aorta α2 smooth muscle actin), ELN (elastin), MYOCD (myocardin), C9orf3 (miR-23b and miR-27b host gene), and MYH11 (smooth muscle myosin). Our analyses also suggest a role in atherosclerosis for developmental transcription factor genes having little or no previous association with atherosclerosis, such as NR2F2 (COUP-TFII) and TBX18. CONCLUSIONS: We provide evidence for atherosclerosis-linked DNA methylation changes in aorta SMCs that might help minimize or reverse the standard contractile character of many of these cells by down-modulating aorta SMC-related enhancers, thereby facilitating pro-atherosclerotic phenotypic changes in many SMCs.
BACKGROUND AND AIMS: Atherosclerosis is a widespread and complicated disease involving phenotypic modulation and transdifferentiation of vascular smooth muscle cells (SMCs), the predominant cells in aorta, as well as changes in endothelial cells and infiltrating monocytes. Alterations in DNA methylation are likely to play central roles in these phenotypic changes, just as they do in normal differentiation and cancer. METHODS: We examined genome-wide DNA methylation changes in atherosclerotic aorta using more stringent criteria for differentially methylated regions (DMRs) than in previous studies and compared these DMRs to tissue-specific epigenetic features. RESULTS: We found that disease-linked hypermethylated DMRs account for 85% of the total atherosclerosis-associated DMRs and often overlap aorta-associated enhancer chromatin. These hypermethylated DMRs were associated with functionally different sets of genes compared to atherosclerosis-linked hypomethylated DMRs. The extent and nature of the DMRs could not be explained as direct effects of monocyte/macrophage infiltration. Among the known atherosclerosis- and contractile SMC-related genes that exhibited hypermethylated DMRs at aorta enhancer chromatin were ACTA2 (aorta α2 smooth muscle actin), ELN (elastin), MYOCD (myocardin), C9orf3 (miR-23b and miR-27b host gene), and MYH11 (smooth muscle myosin). Our analyses also suggest a role in atherosclerosis for developmental transcription factor genes having little or no previous association with atherosclerosis, such as NR2F2 (COUP-TFII) and TBX18. CONCLUSIONS: We provide evidence for atherosclerosis-linked DNA methylation changes in aorta SMCs that might help minimize or reverse the standard contractile character of many of these cells by down-modulating aorta SMC-related enhancers, thereby facilitating pro-atherosclerotic phenotypic changes in many SMCs.
Authors: María del Pilar Valencia-Morales; Silvio Zaina; Holger Heyn; F Javier Carmona; Nuray Varol; Sergi Sayols; Enric Condom; José Ramírez-Ruz; Antonio Gomez; Sebastian Moran; Gertrud Lund; Dalia Rodríguez-Ríos; Gladys López-González; Magda Ramírez-Nava; Carmen de la Rocha; Alejandro Sanchez-Flores; Manel Esteller Journal: BMC Med Genomics Date: 2015-02-27 Impact factor: 3.063
Authors: Kate R Rosenbloom; Joel Armstrong; Galt P Barber; Jonathan Casper; Hiram Clawson; Mark Diekhans; Timothy R Dreszer; Pauline A Fujita; Luvina Guruvadoo; Maximilian Haeussler; Rachel A Harte; Steve Heitner; Glenn Hickey; Angie S Hinrichs; Robert Hubley; Donna Karolchik; Katrina Learned; Brian T Lee; Chin H Li; Karen H Miga; Ngan Nguyen; Benedict Paten; Brian J Raney; Arian F A Smit; Matthew L Speir; Ann S Zweig; David Haussler; Robert M Kuhn; W James Kent Journal: Nucleic Acids Res Date: 2014-11-26 Impact factor: 19.160
Authors: Xiaofeng Cui; Yao Wei Lu; Vivian Lee; Diana Kim; Taylor Dorsey; Qingjie Wang; Young Lee; Peter Vincent; John Schwarz; Guohao Dai Journal: Sci Rep Date: 2015-11-05 Impact factor: 4.379
Authors: Keith A Strand; Sizhao Lu; Marie F Mutryn; Linfeng Li; Qiong Zhou; Blake T Enyart; Austin J Jolly; Allison M Dubner; Karen S Moulton; Raphael A Nemenoff; Keith A Koch; Daniel V LaBarbera; Mary C M Weiser-Evans Journal: Arterioscler Thromb Vasc Biol Date: 2020-06-25 Impact factor: 8.311