New advances of DNA methylation and histone modifications in rheumatoid arthritis, with special emphasis on MeCP2

Abstract

Epigenetics is a steadily growing research area in many human diseases, especially in autoimmune diseases such as rheumatoid arthritis (RA). RA is an autoimmune disease with unclear etiology characterized by chronic inflammation and joint destruction and fibroblast-like synoviocytes (FLS) display a crucial role in the pathogenesis of RA. Even though the etiology is not yet fully understood, RA is generally considered to be caused by a combination of epigenetic modification, deregulated immunomodulation, and environmental factors. Epigenetic modifications, including DNA methylation and post-translational histone modifications, such as histone methylation and histone (de)acetylation are identified as regulatory mechanisms in controlling aggressive FLS activation in patients and animal models. In the last 3 years, the field of epigenetics in RA has impressively increased. Methyl-CpG-binding protein 2 (MeCP2) is first identified as a transcriptional repressor that inhibits gene expression through the interpretation of two epigenetic markers, DNA methylation and histone modification. The cooperative action among MeCP2, DNA methylation and histone modifications indicates that MeCP2 should participate in the pathogenesis of RA through silence of certain gene transcription. In this review, we consider the role of DNA methylation and histone modifications in the development of RA, with a special focus on increased MeCP2 expression in RA animal models.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints. The main characteristic of this autoimmune-related disorder is the hyperplastic and thickened synovium composed of infiltrating inflammatory cells and activated fibroblast-like synoviocytes (FLS) [1]. Besides chemokines and cytokines that enhance the synovium inflammation, resident cells have an ability to synthesize matrix-degrading enzymes and other protein, such as metalloproteinases, which eventually causes a progressive destruction of articular cartilage and bone [2]. RA FLS are leading cells in joint erosion and contribute actively to chronic inflammation and joint destruction. In normal individuals, the synovial lining at the border to the joint cavity consists of 1–3 cell layers, predominantly containing FLS and macrophages. In RA, the lining thickness increases to 10–15 cell layers [3], [4]. Although the understanding of the pathogenesis of RA is not clear, it is generally accepted that it arises from an interplay of epigenetic modification, immunological deregulation and environmental factors.

Epigenetic modification is a novel area of research in RA pathogenesis and is defined as heritable changes in gene expression patterns that are not caused by changes in the primary DNA sequence. Today, this definition has broadened to transient changes in gene expression [5]. Although all cells of an organism have the same DNA sequence, they can differentiate into a multitude of diverse cell types [6]. Epigenetic regulation has a crucial role in this process. As we know, DNA inside a eukaryotic cell is wrapped around an octamer of the core histones H2A, H2B, H3, and H4, thus building the nucleosome, a fundamental unit of chromatin [7]. Epigenetic modifications of the cytosine and the protruding histone tails determine the accessibility of the chromatin and the ability of transcription factors to bind and initiate gene expression [8]. The modification targets are frequently not stable and can rapidly change in response to a stimulus such as environmental factors and aging [9], [10]. It is becoming increasingly clear that epigenetic modifications play a crucial role in the pathogenesis of RA and the study of epigenetics in RA help us to understand why some genetically predisposed individuals tend to suffer from RA while others do not, why some RA patients respond to presently available medication and others do not or how chronic synovitis and articular cartilage erosion are sustained.

MeCP2 was first identified as a transcriptional repressor that inhibits gene expression through the interpretation of DNA methylation and histone deacetylation. The protein encoded by the MeCP2 gene contains a methyl-CpG-binding domain (MBD) and a transcriptional repression domain (TRD). The MBD binds to symmetrically methylated cytosines and the TRD interacts with corepressor proteins, including specific histone deacetylases (HDACs) and mSin3a [11]. This cooperative action among MeCP2, HDACs and DNA methylation suggests a mechanistic link between chromatin modifications and DNA methylation resulting in silence of certain gene transcription. It is confirmed that mutations in the MeCP2 gene lead to the neurodevelopmental disorder Rett syndrome (RTT) [12]. Much research has focused on how mutations in a ubiquitously expressed transcriptional repressor can result in specific neuronal deficits. This review will discuss the DNA methylation and histone modifications in RA development, as well as a potential important role for MeCP2 and epigenetic processes involved in mediating transcriptional repression in the pathogenesis of RA.