Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Nat Commun. 2024 Mar 7;15(1):2106. doi: 10.1038/s41467-024-46181-3.
In all terrestrial vertebrates, the parathyroid glands are critical regulators of calcium homeostasis and the sole source of parathyroid hormone (PTH). Hyperparathyroidism and hypoparathyroidism are clinically important disorders affecting multiple organs. However, our knowledge regarding regulatory mechanisms governing the parathyroids has remained limited. Here, we present the comprehensive maps of the chromatin landscape of the human parathyroid glands, identifying active regulatory elements and chromatin interactions. These data allow us to define regulatory circuits and previously unidentified genes that play crucial roles in parathyroid biology. We experimentally validate candidate parathyroid-specific enhancers and demonstrate their integration with GWAS SNPs for parathyroid-related diseases and traits. For instance, we observe reduced activity of a parathyroid-specific enhancer of the Calcium Sensing Receptor gene, which contains a risk allele associated with higher PTH levels compared to the wildtype allele. Our datasets provide a valuable resource for unraveling the mechanisms governing parathyroid gland regulation in health and disease.
在所有的陆生脊椎动物中，甲状旁腺是钙稳态的关键调节剂，也是甲状旁腺激素（PTH）的唯一来源。甲状旁腺功能亢进症和甲状旁腺功能减退症是影响多个器官的临床重要疾病。然而，我们对于调节甲状旁腺的调控机制的了解仍然有限。在这里，我们呈现了人类甲状旁腺染色质景观的综合图谱，确定了活跃的调控元件和染色质相互作用。这些数据使我们能够定义调控回路和以前未被识别的基因，这些基因在甲状旁腺生物学中起着至关重要的作用。我们通过实验验证了候选甲状旁腺特异性增强子，并证明了它们与与甲状旁腺相关的疾病和特征相关的 GWAS SNPs 的整合。例如，我们观察到钙感应受体基因的一个甲状旁腺特异性增强子的活性降低，该增强子包含一个与野生型等位基因相比，与更高的 PTH 水平相关的风险等位基因。我们的数据集为揭示健康和疾病中甲状旁腺调节的机制提供了宝贵的资源。
