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Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential

Abstract

Systemic sclerosis (SSc) is a prototypical inflammatory fibrotic disease involving inflammation, vascular abnormalities and fibrosis that primarily affect the skin and lungs. The aetiology of SSc is unknown and its pathogenesis is only partially understood. Of all the rheumatic diseases, SSc carries the highest all-cause mortality rate and represents an unmet medical need. A growing body of evidence implicates epigenetic aberrations in this intractable disease, including specific modifications affecting the three main cell types involved in SSc pathogenesis: immune cells, endothelial cells and fibroblasts. In this Review, we discuss the latest insights into the role of DNA methylation, histone modifications and non-coding RNAs in SSc and how these epigenetic alterations affect disease features. In particular, histone modifications have a role in the regulation of gene expression pertinent to activation of fibroblasts to myofibroblasts, governing their fate. DNA methyltransferases are crucial in disease pathogenesis by mediating methylation of DNA in specific promoters, regulating expression of specific pathways. We discuss targeting of these enzymes for therapeutic gain. Innovative epigenetic therapy could be targeted to treat the disease in a precision epigenetics approach.

Key points

  • In systemic sclerosis (SSc), epigenetic aberrations are prominent in the main cell types involved in the disease pathogenesis.

  • DNA in SSc fibroblasts seems to be hypermethylated, leading to repression of gene expression of negative regulators such as SOCS3.

  • Studies of open regions of chromatin using ATAC sequencing have identified multiple regions of transcriptionally active genes, although their function (or functions) needs further investigation in understanding the role in SSc pathogenesis.

  • Non-coding RNAs, including long non-coding RNAs and microRNAs, have been linked to SSc in the past few years and might be targets for anti-fibrotic therapy through alteration of their levels.

  • Epigenetic drugs already in use for other indications, such as decitabine, could be repurposed for SSc.

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Fig. 1: Epigenetic mechanisms.
Fig. 2: Cell type-specific epigenetic aberrations in systemic sclerosis.

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S.O. researched data for the article. All authors made substantial contributions to discussions of the content and contributed to writing the article and reviewing/editing of the manuscript before submission.

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Correspondence to Steven O’Reilly.

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S.O. became a full-time employee of Stipe Therapeutics after submission of this manuscript. The other authors declare no competing interests.

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Nature Reviews Rheumatology thanks Y. Asano, B. Kahaleh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Methyl binding domain

A family of methyl-CpG-binding domain proteins that translate the DNA methylation signal and that work in concert with other proteins such as histone deacetyl transferases to facilitate gene repression.

Histone tails

Flexible regions that flank both ends of the histone fold and that can be modified by a plethora of modifications that impact chromatin dynamics and gene expression.

Lactylation

An epigenetic modification whereby the metabolite lactate is deposited on histone lysine residues.

Histone acetyl transferases

(HATs). A group of enzymes that mediate the addition of an acetyl group onto lysine residues on histones to modulate gene expression.

Histone deacetyl transferases

(HDACs). A group of enzymes that mediate the removal of acetyl groups from lysine residues on histones, positively regulating gene expression.

Stress fibres

Contractile actin bundles found in non-muscle cells, composed of actin and non-muscle myosin II.

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Tsou, PS., Varga, J. & O’Reilly, S. Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential. Nat Rev Rheumatol 17, 596–607 (2021). https://doi.org/10.1038/s41584-021-00683-2

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