Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London SE19RT, UK.
Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London SE19RT, UK.
Genes (Basel). 2021 Mar 30;12(4):509. doi: 10.3390/genes12040509.
In mammals, imprinted genes regulate many critical endocrine processes such as growth, the onset of puberty and maternal reproductive behaviour. Human imprinting disorders (IDs) are caused by genetic and epigenetic mechanisms that alter the expression dosage of imprinted genes. Due to improvements in diagnosis, increasing numbers of patients with IDs are now identified and monitored across their lifetimes. Seminal work has revealed that IDs have a strong endocrine component, yet the contribution of imprinted gene products in the development and function of the hypothalamo-pituitary axis are not well defined. Postnatal endocrine processes are dependent upon the production of hormones from the pituitary gland. While the actions of a few imprinted genes in pituitary development and function have been described, to date there has been no attempt to link the expression of these genes as a class to the formation and function of this essential organ. This is important because IDs show considerable overlap, and imprinted genes are known to define a transcriptional network related to organ growth. This knowledge deficit is partly due to technical difficulties in obtaining useful transcriptomic data from the pituitary gland, namely, its small size during development and cellular complexity in maturity. Here we utilise high-sensitivity RNA sequencing at the embryonic stages, and single-cell RNA sequencing data to describe the imprinted transcriptome of the pituitary gland. In concert, we provide a comprehensive literature review of the current knowledge of the role of imprinted genes in pituitary hormonal pathways and how these relate to IDs. We present new data that implicate imprinted gene networks in the development of the gland and in the stem cell compartment. Furthermore, we suggest novel roles for individual imprinted genes in the aetiology of IDs. Finally, we describe the dynamic regulation of imprinted genes in the pituitary gland of the pregnant mother, with implications for the regulation of maternal metabolic adaptations to pregnancy.
在哺乳动物中，印迹基因调节许多关键的内分泌过程，如生长、青春期的开始和母性生殖行为。人类印迹疾病（IDs）是由遗传和表观遗传机制引起的，这些机制改变了印迹基因的表达剂量。由于诊断水平的提高，现在有越来越多的 IDs 患者在其一生中被发现并监测。开创性的工作表明，IDs 具有很强的内分泌成分，但印迹基因产物在下丘脑-垂体轴的发育和功能中的作用尚未得到很好的定义。出生后的内分泌过程依赖于垂体分泌的激素。虽然已经描述了少数印迹基因在垂体发育和功能中的作用，但迄今为止，还没有人试图将这些基因的表达作为一个类别与这个重要器官的形成和功能联系起来。这很重要，因为 IDs 表现出相当大的重叠，并且已知印迹基因定义了与器官生长相关的转录网络。这种知识上的差距部分是由于从垂体获得有用的转录组数据的技术困难，即其在发育过程中的体积小和成熟时的细胞复杂性。在这里，我们利用胚胎期的高灵敏度 RNA 测序和单细胞 RNA 测序数据来描述垂体的印迹转录组。同时，我们对印迹基因在垂体激素途径中的作用以及这些作用如何与 IDs 相关的现有知识进行了全面的文献综述。我们提出了新的数据，表明印迹基因网络参与了腺体的发育和干细胞区室。此外，我们提出了个别印迹基因在 IDs 病因学中的新作用。最后，我们描述了印迹基因在怀孕母亲垂体中的动态调节，这对调节母体代谢适应妊娠具有重要意义。
