Characterization of comprehensive dynamic epigenetic changes during human primary Sjögren's syndrome progression

Abstract

Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by reduced exocrine gland (principally the salivary and lacrimal glands) activity caused by chronic lymphocytic infiltration. Although pSS has been closely associated with an increased risk of mucosa-associated lymphoid tissue (MALT) lymphoma, the dynamic epigenetic changes in the gland cells that accompany the pathogenesis are not entirely understood.

Methods: In this study, we harvested tissue samples from the labial gland with (LG_pSS) or without pSS (LG_NC) before MALT development, as well as the parotid gland with tumor tissues (PG_MALT) and paracancerous tissues (PG_NC) of two pSS patients with MALT lymphoma, and conducted RNA-seq and ChIP-seq for tri-methylated histone 3 lysine 4, 9, 27, 36, and 79 (H3K4/9/27/36/79me3).

Results: Transcriptome landscapes indicated two outcomes of pSS progression with or without MALT lymphoma represented by distinct populations of differentially expressed genes and their functions. Furthermore, the epigenetic atlas of genome-wide H3K4/9/27/36/79me3 was in different stages for various samples, indicating that the variance of H3K4me3 was the earliest event, followed by selective alterations of H3K9/27/36/79me3. These four epigenetic modifications determine the final outcome of pSS progression.

Conclusions: Our results not only advance the understanding of the dynamics of pSS progression and highlight the importance of epigenetic alterations in regulating transcription during this pathological process, but also identify potential therapeutic targets for pSS treatment and lymphoma intervention.

Keywords: Primary Sjögren’s syndrome (pSS); epigenetic regulation; mucosa-associated lymphoid tissue lymphoma (MALT lymphoma).

Figure 1

Transcriptome landscape of pSS development. (A) Schematic illustration of the comprehensive analysis. (B) Global transcriptome analysis based on 16 RNA-seq reads for LG_NC, LG_pSS, PG_NC, and PG_MALT. (C) The distribution of correlation coefficients among DEGs from two-group comparisons. The displayed count of DEGs depends on the group with fewer DEGs. (D) The intersection of DEGs of the comparison among LG_NC, LG_pSS, PG_NC and PG_MALT. (E) Bubble plots for the enriched GO functions of DEGs. pSS, primary Sjögren’s syndrome; LG_NC, labial gland with negative lymphocyte infiltration; LG_pSS, labial gland with positive lymphocyte infiltration; PG_NC, paracancerous parotid gland tissues; PG_MALT, parotid gland with MALT lymphoma tissues; H3K4/9/27/36/79me3, tri-methylated histone 3 lysine 4, 9, 27, 36, and 79; DEGs, differentially expressed genes.

Figure 2

Overview of genome-wide histone modifications in pSS progression. (A) Total peak numbers of the histone modifications H3K4/9/27/36/79me3 in different pSS samples. *P<0.05. (B) Metagene profiles of genome-wide H3K4/9/27/36/79me3 during pSS progression. (C) Pearson correlation analysis between transcription levels and different histone modifications for all DEGs in Routes 1 and 2. pSS, primary Sjögren’s syndrome; H3K4/9/27/36/79me3, tri-methylated histone 3 lysine 4, 9, 27, 36, and 79; TSS, transcription start site; TES, transcription end site; PCC, Pearson correlation coefficient.

Figure 3

Regulatory effects of different histone modifications on gene expression. (A) The closer analysis among different histone modifications on DEGs. (B) The effects of histone modification changes on gene expression during pSS progression. Gene browser views of histone modifications on AQP1 (C) and TRAF6 (D). pSS, primary Sjögren’s syndrome; H3K4/9/27/36/79me3, tri-methylated histone 3 lysine 4, 9, 27, 36, and 79; PCC, Pearson correlation coefficient. AQP1, aquaporin 1; TRAF6, TNF receptor associated factor 6.

Figure 4

Proposed scheme of the histone modification landscapes over the course of pSS progression. pSS, primary Sjögren’s syndrome; H3K4/9/27/36/79me3, tri-methylated histone 3 lysine 4, 9, 27, 36, and 79.