DNA Methylation As a Transcriptional Regulator of the Immune System

Overview

Journal Transl Res

Publisher Elsevier

Specialty Pathology

Date 2018 Sep 1

PMID 30170004

Citations 67

Authors

Luisa Morales-Nebreda

Fred S McLafferty

Benjamin D Singer

Affiliations

Soon will be listed here.

Abstract

DNA methylation is a dynamic epigenetic modification with a prominent role in determining mammalian cell development, lineage identity, and transcriptional regulation. Primarily linked to gene silencing, novel technologies have expanded the ability to measure DNA methylation on a genome-wide scale and uncover context-dependent regulatory roles. The immune system is a prototypic model for studying how DNA methylation patterning modulates cell type- and stimulus-specific transcriptional programs. Preservation of host defense and organ homeostasis depends on fine-tuned epigenetic mechanisms controlling myeloid and lymphoid cell differentiation and function, which shape innate and adaptive immune responses. Dysregulation of these processes can lead to human immune system pathology as seen in blood malignancies, infections, and autoimmune diseases. Identification of distinct epigenotypes linked to pathogenesis carries the potential to validate therapeutic targets in disease prevention and management.

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References

Bird A . DNA methylation patterns and epigenetic memory. Genes Dev. 2002; 16(1):6-21. DOI: 10.1101/gad.947102. View

Del Campo R, Martinez E, Del Fresno C, Alenda R, Gomez-Pina V, Fernandez-Ruiz I . Translocated LPS might cause endotoxin tolerance in circulating monocytes of cystic fibrosis patients. PLoS One. 2012; 6(12):e29577. PMC: 3247277. DOI: 10.1371/journal.pone.0029577. View

Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M . Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009; 114(1):144-7. PMC: 2710942. DOI: 10.1182/blood-2009-03-210039. View

Azad N, Zahnow C, Rudin C, Baylin S . The future of epigenetic therapy in solid tumours--lessons from the past. Nat Rev Clin Oncol. 2013; 10(5):256-66. PMC: 3730253. DOI: 10.1038/nrclinonc.2013.42. View

Silverman L, Demakos E, Peterson B, Kornblith A, Holland J, Odchimar-Reissig R . Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002; 20(10):2429-40. DOI: 10.1200/JCO.2002.04.117. View

Falini B, Nicoletti I, Martelli M, Mecucci C . Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2006; 109(3):874-85. DOI: 10.1182/blood-2006-07-012252. View

Rawstron A, Bennett F, OConnor S, Kwok M, Fenton J, Plummer M . Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008; 359(6):575-83. DOI: 10.1056/NEJMoa075290. View

Genovese G, Kahler A, Handsaker R, Lindberg J, Rose S, Bakhoum S . Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014; 371(26):2477-87. PMC: 4290021. DOI: 10.1056/NEJMoa1409405. View

Figueroa M, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos P . DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010; 17(1):13-27. PMC: 3008568. DOI: 10.1016/j.ccr.2009.11.020. View

10.

Lian X, Xiao R, Hu X, Kanekura T, Jiang H, Li Y . DNA demethylation of CD40l in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum. 2012; 64(7):2338-45. DOI: 10.1002/art.34376. View

11.

Ayton P, Cleary M . Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 2003; 17(18):2298-307. PMC: 196466. DOI: 10.1101/gad.1111603. View

12.

Hino R, Uozaki H, Murakami N, Ushiku T, Shinozaki A, Ishikawa S . Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res. 2009; 69(7):2766-74. DOI: 10.1158/0008-5472.CAN-08-3070. View

13.

Paul D, Beck S . Advances in epigenome-wide association studies for common diseases. Trends Mol Med. 2014; 20(10):541-3. PMC: 4186777. DOI: 10.1016/j.molmed.2014.07.002. View

14.

Gross S, Cairns R, Minden M, Driggers E, Bittinger M, Jang H . Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010; 207(2):339-44. PMC: 2822606. DOI: 10.1084/jem.20092506. View

15.

Kim H, Leonard W . CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med. 2007; 204(7):1543-51. PMC: 2118651. DOI: 10.1084/jem.20070109. View

16.

Bennett C, Christie J, Ramsdell F, Brunkow M, Ferguson P, Whitesell L . The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001; 27(1):20-1. DOI: 10.1038/83713. View

17.

Ciferska H, Horak P, Hermanova Z, Ordeltova M, Zadrazil J, Tichy T . The levels of sCD30 and of sCD40L in a group of patients with systemic lupus erythematodes and their diagnostic value. Clin Rheumatol. 2006; 26(5):723-8. DOI: 10.1007/s10067-006-0389-9. View

18.

Broske A, Vockentanz L, Kharazi S, Huska M, Mancini E, Scheller M . DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet. 2009; 41(11):1207-15. DOI: 10.1038/ng.463. View

19.

Laird P . Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet. 2010; 11(3):191-203. DOI: 10.1038/nrg2732. View

20.

Pacis A, Tailleux L, Morin A, Lambourne J, MacIsaac J, Yotova V . Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res. 2015; 25(12):1801-11. PMC: 4665002. DOI: 10.1101/gr.192005.115. View