Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
Division of Gastroenterology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Sci Rep. 2018 Apr 4;8(1):5649. doi: 10.1038/s41598-018-23957-4.
In humans the expression of lactase changes during post-natal development, leading to phenotypes known as lactase persistence and non-persistence. Polymorphisms within the lactase gene (LCT) enhancer, in particular the -13910C > T, but also others, are linked to these phenotypes. We were interested in identifying dynamic mediators of LCT regulation, beyond the genotype at -13910C > T. To this end, we investigated two levels of lactase regulation in human intestinal samples obtained from New England children and adolescents of mixed European ancestry: differential expression of transcriptional regulators of LCT, and variations in DNA methylation, and their relation to phenotype. Variations in expression of CDX2, POU2F1, GATA4, GATA6, and HNF1α did not correlate with phenotype. However, an epigenome-wide approach using the Illumina Infinium HM450 bead chip identified a differentially methylated position in the LCT promoter where methylation levels are associated with the genotype at -13910C > T, the persistence/non-persistence phenotype and lactase enzymatic activity. DNA methylation levels at this promoter site and CpGs in the LCT enhancer are associated with genotype. Indeed, taken together they have a higher power to predict lactase phenotypes than the genotype alone.
在人类的出生后发育过程中，乳糖酶的表达会发生变化，导致出现乳糖酶持续存在和不持续存在两种表型。乳糖酶基因（LCT）增强子中的多态性，特别是-13910C>T，但也有其他多态性，与这些表型有关。我们感兴趣的是确定 LCT 调节的动态介质，而不仅仅是 -13910C>T 基因型。为此，我们研究了从新英格兰具有混合欧洲血统的儿童和青少年获得的人类肠道样本中乳糖酶调节的两个水平：LCT 转录调节因子的差异表达，以及 DNA 甲基化的变化，及其与表型的关系。CDX2、POU2F1、GATA4、GATA6 和 HNF1α 的表达变化与表型无关。然而，使用 Illumina Infinium HM450 珠芯片进行的全基因组表观遗传方法确定了 LCT 启动子中一个差异甲基化的位置，该位置的甲基化水平与 -13910C>T 基因型、持续/非持续表型和乳糖酶酶活性有关。该启动子位点和 LCT 增强子中的 CpG 处的 DNA 甲基化水平与基因型有关。事实上，它们共同预测乳糖酶表型的能力高于单独的基因型。
