Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
J Diabetes Investig. 2019 Jan;10(1):51-61. doi: 10.1111/jdi.12867. Epub 2018 Jun 26.
AIMS/INTRODUCTION: Genetic and epigenetic mechanisms have been implicated in the pathogenesis of type 1 diabetes, and histone acetylation is an epigenetic modification pattern that activates gene transcription. However, the genome-wide histone H3 acetylation in new-onset type 1 diabetes patients has not been well described. Accordingly, we aimed to unveil the genome-wide promoter acetylation profile in CD4 T lymphocytes from type 1 diabetes patients, especially for those who are glutamate decarboxylase antibody-positive.
A total of 12 patients with new-onset type 1 diabetes who were glutamate decarboxylase antibody-positive were enrolled, and 12 healthy individuals were recruited as controls. The global histone H3 acetylation level of CD4 T lymphocytes from peripheral blood was detected by western blot, with chromatin immunoprecipitation linked to microarrays to characterize the promoter acetylation profile. Furthermore, we validated the results of particular genes from chromatin immunoprecipitation linked to microarrays by using chromatin immunoprecipitation quantitative polymerase chain reaction, and analyzed the transcription level by real-time quantitative polymerase chain reaction.
Elevated global histone H3 acetylation level was observed in type 1 diabetes patients, with 607 differentially acetylated genes identified between type 1 diabetes patients and controls by chromatin immunoprecipitation linked to microarrays. The hyperacetylated genes were enriched in biological processes involved in immune cell activation and inflammatory response. Gene-specific assessments showed that increased transcription of inducible T-cell costimulator was in concordance with the elevated acetylation in its gene promoter, along with positive correlation with glutamate decarboxylase antibody titer in type 1 diabetes patients.
The present study generates a genome-wide histone acetylation profile specific to CD4 T lymphocytes in type 1 diabetes patients who are glutamic acid decarboxylase antibody-positive, which is instrumental in improving our understanding of the epigenetic involvement in autoimmune diabetes.
目的/引言：遗传和表观遗传机制与 1 型糖尿病的发病机制有关，组蛋白乙酰化是一种激活基因转录的表观遗传修饰模式。然而，新诊断的 1 型糖尿病患者中全基因组组蛋白 H3 乙酰化尚未得到很好的描述。因此，我们旨在揭示谷氨酸脱羧酶抗体阳性的 1 型糖尿病患者 CD4 T 淋巴细胞中的全基因组启动子乙酰化谱，特别是针对那些谷氨酸脱羧酶抗体阳性的患者。
共纳入 12 例新诊断的谷氨酸脱羧酶抗体阳性的 1 型糖尿病患者，招募 12 例健康个体作为对照。通过 Western blot 检测外周血 CD4 T 淋巴细胞的整体组蛋白 H3 乙酰化水平，并用染色质免疫沉淀结合微阵列来描述启动子乙酰化谱。此外，我们使用染色质免疫沉淀定量聚合酶链反应验证了染色质免疫沉淀结合微阵列的特定基因的结果，并通过实时定量聚合酶链反应分析了转录水平。
我们观察到 1 型糖尿病患者的整体组蛋白 H3 乙酰化水平升高，通过染色质免疫沉淀结合微阵列在 1 型糖尿病患者和对照组之间鉴定出 607 个差异乙酰化基因。超乙酰化基因富集在涉及免疫细胞激活和炎症反应的生物学过程中。基因特异性评估表明，诱导型 T 细胞共刺激因子的转录增加与基因启动子中的乙酰化增加一致，并且与谷氨酸脱羧酶抗体滴度在 1 型糖尿病患者中呈正相关。
本研究生成了谷氨酸脱羧酶抗体阳性的 1 型糖尿病患者 CD4 T 淋巴细胞的全基因组组蛋白乙酰化谱，有助于我们更好地了解自身免疫性糖尿病中的表观遗传参与。
