Laverrière Jean-Noël, L'Hôte David, Tabouy Laure, Schang Anne-Laure, Quérat Bruno, Cohen-Tannoudji Joëlle
Univ Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013, Paris, France; CNRS UMR 8251, F-75013, Paris, France; Physiologie de l'axe gonadotrope INSERM U1133, F-75013, Paris, France.
Univ Paris Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative (BFA), F-75013, Paris, France; CNRS UMR 8251, F-75013, Paris, France; Physiologie de l'axe gonadotrope INSERM U1133, F-75013, Paris, France.
Mol Cell Endocrinol. 2016 Oct 15;434:250-65. doi: 10.1016/j.mce.2016.07.010. Epub 2016 Jul 9.
Gonadotrope cell identity genes emerge in a stepwise process during mouse pituitary development. Cga, encoding for the α-subunit of TSH, LH, and FSH, is initially detected at E11.5 followed by Gnrhr and steroidogenic factor Sf1 at E13.5, specifying cells engaged in a gonadotrope cell fate. Lhb and Fshb appear at E16.5 and 17.5, respectively, typifying differentiated gonadotrope cells. Using the αT1-1, αT3-1 and LβT2 cell lines recapitulating these stages of gonadotrope differentiation, DNA methylation at Gnrhr and Sf1 was investigated. Regulatory regions were found hypermethylated in progenitor αT1-1 cells and hypomethylated in differentiated LβT2 cells. Abundance of RNA polymerase II together with active histone modifications including H3K4me1, H3K4me3, and H3K27ac were strictly correlated with DNA hypomethylation. Analyses of epigenomic modifications and chromatin accessibility were further extended to Isl1, Lhx3, Gata2, and Pitx2, highlighting alternative usages of specific regulatory gene domains in progenitor αT1-1, immature αT3-1, and mature LβT2 gonadotrope cells.
促性腺激素细胞身份基因在小鼠垂体发育过程中以逐步的方式出现。编码促甲状腺激素、促黄体生成素和促卵泡激素α亚基的Cga最初在胚胎第11.5天被检测到，随后在胚胎第13.5天检测到促性腺激素释放激素受体（Gnrhr）和类固醇生成因子Sf1，确定了参与促性腺激素细胞命运的细胞。促黄体生成素β亚基（Lhb）和促卵泡激素β亚基（Fshb）分别在胚胎第16.5天和17.5天出现，代表分化的促性腺激素细胞。利用αT1-1、αT3-1和LβT2细胞系重现促性腺激素细胞分化的这些阶段，研究了Gnrhr和Sf1处的DNA甲基化。发现调控区域在祖细胞αT1-1中高度甲基化，而在分化的LβT2细胞中低甲基化。RNA聚合酶II的丰度以及包括H3K4me1、H3K4me3和H3K27ac在内的活性组蛋白修饰与DNA低甲基化严格相关。表观基因组修饰和染色质可及性分析进一步扩展到Isl-1、Lhx3、Gata2和Pitx2，突出了祖细胞αT1-1、未成熟αT3-1和成熟LβT2促性腺激素细胞中特定调控基因域的不同使用情况。
