Cattini Peter A, Jin Yan
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
Int J Mol Sci. 2025 May 6;26(9):4421. doi: 10.3390/ijms26094421.
The human (h) growth hormone (GH)/placental lactogen (PL) gene family has served as an important model to study tissue-specific expression. The two GH genes (/ and /) and three PL or chorionic somatomammotropin hormone (CSH) genes (/, / and /) are clustered together at a single locus. Although they share >90% sequence similarity, is expressed by somatotrophs of the anterior pituitary while the remaining four hGH/PL genes are expressed by the villous syncytiotrophoblast of the placenta. Efficient pituitary expression depends on a locus control region (LCR) that includes nuclease hypersensitive sites I-V (HS I-V). For activation, data indicate that HS III facilitates the initial access of pituitary-specific transcription factor Pit-1 to the locus, where it is required to bind Pit-1 sites at HS I/II and the promoter. This is associated with histone acetylation and tri-methylation modifications that are consistent with active chromatin. However, all five hGH/PL genes share similar nuclease sensitivity in human pituitary chromatin, suggesting similar levels of accessibility and thus potential for transcription. Furthermore, and promoters contain Pit-1 binding sites, and the promoter, like , will support expression in transfected pituitary tumor GC cells in culture. These observations suggest the possibility of a transcriptional repressor mechanism that prevents hPL gene expression in the pituitary. P sequences were identified as a candidate. They are located upstream of all four placental hGH/PL genes but not , repress promoter activity in transfected pituitary GC cells, and bind a forkhead box A1/nuclear factor-1 transcription, which is proposed to act as a repressor complex in human pituitary chromatin. In spite of this, the inability to limit expression when tested in transgenic mice brought the role of P sequences in pituitary repression into question. These observations are re-examined here in light of new evidence that the LCR (HS III) interacts with P sequences in the human pituitary.
人类（h）生长激素（GH）/胎盘催乳素（PL）基因家族一直是研究组织特异性表达的重要模型。两个GH基因（/和/）以及三个PL或绒毛膜生长催乳素（CSH）基因（/、/和/）在单个位点聚集在一起。尽管它们的序列相似性超过90%，但 由垂体前叶的促生长激素细胞表达，而其余四个hGH/PL基因由胎盘的绒毛合体滋养层表达。有效的垂体表达依赖于一个基因座控制区（LCR），该区域包括核酸酶超敏位点I-V（HS I-V）。关于激活，数据表明HS III促进垂体特异性转录因子Pit-1最初与该基因座结合，在该基因座上，Pit-1需要结合HS I/II和 启动子处的Pit-1位点。这与组蛋白乙酰化和三甲基化修饰有关，这些修饰与活性染色质一致。然而，所有五个hGH/PL基因在人垂体染色质中具有相似的核酸酶敏感性，表明可及性水平相似，因此具有转录潜力。此外， 和 启动子含有Pit-1结合位点，并且 启动子与 一样，在培养的转染垂体肿瘤GC细胞中支持表达。这些观察结果提示存在一种转录抑制机制，可阻止垂体中hPL基因的表达。P序列被确定为一个候选因素。它们位于所有四个胎盘hGH/PL基因的上游，但不位于 上游，在转染的垂体GC细胞中抑制 启动子活性，并结合叉头框A1/核因子-1转录，该转录因子被认为在人垂体染色质中作为一种抑制复合物起作用。尽管如此，在转基因小鼠中进行测试时无法限制 表达，这使得P序列在垂体抑制中的作用受到质疑。鉴于新的证据表明LCR（HS III）与人垂体中的P序列相互作用，在此重新审视这些观察结果。
