Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
J Clin Endocrinol Metab. 2018 Dec 1;103(12):4617-4627. doi: 10.1210/jc.2018-00052.
Inactivating mutations within the AR gene are present in only ~40% of individuals with clinically and hormonally diagnosed androgen insensitivity syndrome (AIS). Previous studies revealed the existence of an AR gene mutation-negative group of patients with AIS who have compromised androgen receptor (AR) function (AIS type II).
To investigate whether AIS type II can be due to epigenetic repression of AR transcription.
Quantification of AR mRNA and AR proximal promoter CpG methylation levels in genital skin-derived fibroblasts (GFs) derived from patients with AIS type II and control individuals.
University hospital endocrine research laboratory.
GFs from control individuals (n = 11) and patients with AIS type II (n = 14).
MAIN OUTCOME MEASURE(S): Measurement of AR mRNA and AR promoter CpG methylation as well as activity of AR proximal promoter in vitro.
Fifty-seven percent of individuals with AIS type II (n = 8) showed a reduced AR mRNA expression in their GFs. A significant inverse correlation was shown between AR mRNA abundance and methylation at two consecutive CpGs within the proximal AR promoter. Methylation of a 158-bp-long region containing these CpGs was sufficient to severely reduce reporter gene expression. This region was bound by the runt related transcription factor 1 (RUNX1). Ectopic expression of RUNX1 in HEK293T cells was able to inhibit reporter gene expression through this region.
Aberrant CpGs methylation within the proximal AR promoter plays an important role in the control of AR gene expression and may result in AIS type II. We suggest that transcriptional modifiers, such as RUNX1, could play roles therein offering new perspectives for understanding androgen-mediated endocrine diseases.
在临床上和激素诊断的雄激素不敏感综合征（AIS）个体中，只有约 40%存在 AR 基因失活突变。先前的研究表明，AIS 存在 AR 基因无突变组的患者，他们的雄激素受体（AR）功能受损（AIS 型 II）。
研究 AIS 型 II 是否是由于 AR 转录的表观遗传抑制所致。
对源自 AIS 型 II 患者和对照个体的生殖器皮肤衍生成纤维细胞（GF）中的 AR mRNA 和 AR 近端启动子 CpG 甲基化水平进行定量。
大学医院内分泌研究实验室。
对照个体（n=11）和 AIS 型 II 患者（n=14）的 GFs。
测量 AR mRNA 和 AR 启动子 CpG 甲基化以及体外 AR 近端启动子活性。
57%的 AIS 型 II 个体（n=8）在其 GFs 中显示 AR mRNA 表达减少。AR mRNA 丰度与 AR 近端启动子中两个连续 CpG 处的甲基化呈显著负相关。包含这些 CpG 的 158bp 长区域的甲基化足以严重降低报告基因的表达。该区域与 runt 相关转录因子 1（RUNX1）结合。在 HEK293T 细胞中外源性表达 RUNX1 能够通过该区域抑制报告基因的表达。
AR 启动子近端的异常 CpG 甲基化在 AR 基因表达的调控中起重要作用，可能导致 AIS 型 II。我们认为，转录调节剂，如 RUNX1，可能在其中发挥作用，为理解雄激素介导的内分泌疾病提供了新的视角。
