Department of Rheumatology, Yantai Yuhuangding Hospital, Yantai, China.
Cell Biol Int. 2021 Feb;45(2):456-462. doi: 10.1002/cbin.11508. Epub 2020 Dec 8.
Dermatomyositis (DM) is characterized as a chronic autoimmune disorder with multiple organ involvement. Our previous study has revealed that Cathepsin G (CTSG) highly expressed in dermatomyositic in vivo is regulated by DNMT3a through DNA methylation of 5'-C-phosphate-G-3' loci at exons and introns. However, the mechanism of gene body methylation on regulating CTSG transcription remains unknown. In this study, we studied quadriceps femoris tissues of six DM patients, and observed that antisense long noncoding RNA AL136018.1 contiguous to CTSG was highly expressed in skeletal muscle tissues of DM and positively correlated with the transcription level and DNA methylation level in gene body of CTSG in vivo. Moreover, we observed that the longer transcript of AL136018.1 (AL136018.1-201) could bind to third and fourth exons and third intron of CTSG via the 3'-end. Finally, AL136018.1-201 could recruit DNMT3a towards gene body via 5'-terminal for adding DNA methylation and facilitating transcription of CTSG. Taken together, our data uncovered a novel epigenetic mechanism behind the gene body methylation for transcriptional regulation of CTSG in DM.
皮肌炎（DM）是一种以多器官受累为特征的慢性自身免疫性疾病。我们之前的研究表明，组织蛋白酶 G（CTSG）在皮肌炎的体内高度表达，受 DNMT3a 通过 5'-C-磷酸-G-3' 位点的 DNA 甲基化调节，该位点位于外显子和内含子。然而，基因体甲基化调节 CTSG 转录的机制尚不清楚。在这项研究中，我们研究了六名 DM 患者的股四头肌组织，观察到与 CTSG 相邻的反义长非编码 RNA AL136018.1 在 DM 骨骼肌组织中高度表达，并且与体内 CTSG 基因体的转录水平和 DNA 甲基化水平呈正相关。此外，我们观察到较长的 AL136018.1 转录本（AL136018.1-201）可以通过 3' 端与 CTSG 的第三和第四外显子以及第三内含子结合。最后，AL136018.1-201 可以通过 5' 端招募 DNMT3a 到基因体，增加 DNA 甲基化并促进 CTSG 的转录。总之，我们的数据揭示了 DM 中 CTSG 转录调控的基因体甲基化背后的一种新的表观遗传机制。
