DNA methylation as a transcriptional regulator of the immune system

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.

Figure 1.. DNA methylation chemistry.

DNA methyltransferases (DNMT) use S-adenosylmethionine as a methyl donor to catalyze the addition of a methyl group to the 5-carbon position of cytosine, resulting in 5-methylcytosine (5mC). 5mC can be read by multiple nuclear proteins that lead to changes in gene expression, including methyl-CpG-binding domain (MBD) proteins; ubiquitin-like, containing PHD and RING finger domains (UHRF) proteins; and other zinc-finger proteins. Demethylation of 5mC back to cytosine can occur passively during cell division. Active demethylation can occur via the ten-eleven translocation (TET) enzymes, which use oxygen, 2-oxoglutarate, and ferrous iron to catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Each reaction generates an oxidized ferric iron, succinate, and carbon dioxide. G/T-mismatch-specific thymine DNA glycosylase (TDG) can then excise 5fC and 5caC, resulting in an apyrimidinic (AP) site. These AP sites can then undergo base excision repair (BER), which replaces cytosine at that position. Not shown are other demethylation pathways including deamination of 5mC or 5hmC by activation-induced deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (AID/APOBEC) family members to form 5-methyluracil (5mU) or 5-hydroxymethyluracil (5hmU), respectively, which can be catalyzed to cytosine via the TDG/BER pathway.

Figure 2.

DNA methylation state during innate and adaptive immune cell development, differentiation and function. Epigenetic modifications, including DNA methylation, modulate the self-renewal capacity of the hematopoietic stem cell pool throughout the lifespan and tightly regulate the hierarchical differentiation process of immune cells. DNA methylation patterning is specific to immune cell types during distinct maturation stages and correlate with a cell’s gene regulatory and functional programs. DNA methyltransferase (DNMT), multipotent progenitors (MPP), common lymphoid progenitors (CLP), common myeloid progenitors (CMP), 5-hydroxymethylcytosine (5hmC), conserved noncoding sequence 2 (CNS2).

Figure 3.

Epigenetic patterns of immune cell subsets in the pathogenesis of autoimmune diseases. Cell-specific methylation changes are linked to immune cell differentiation and function during the development of autoimmune processes. Epigenetic marks can identify subjects at increased risk for organ damage, disease progression and overall mortality in these human pathologies. Systemic lupus erythematosus (SLE), systemic sclerosis (SSc), regulatory T cells (Treg cells), glomerulonephritis (GN), TFs (transcription factors).