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首页> 外文期刊>Molecular and Cellular Biology >Evidence for a Bigenic Chromatin Subdomain in Regulation of the Fetal-to-Adult Hemoglobin Switch
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Evidence for a Bigenic Chromatin Subdomain in Regulation of the Fetal-to-Adult Hemoglobin Switch

机译：胎儿至成人血红蛋白开关调节中的生物染色质子域的证据。

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During development, human β-globin locus regulation undergoes two critical switches, the embryonic-to-fetal and fetal-to-adult hemoglobin switches. To define the role of the fetal Aγ-globin promoter in switching, human β-globin-YAC transgenic mice were produced with the Aγ-globin promoter replaced by the erythroid porphobilinogen deaminase (PBGD) promoter (PBGDAγ-YAC). Activation of the stage-independent PBGDAγ-globin strikingly stimulated native Gγ-globin expression at the fetal and adult stages, identifying a fetal gene pair or bigenic cooperative mechanism. This impaired fetal silencing severely suppressed both δ- and β-globin expression in PBGDAγ-YAC mice from fetal to neonatal stages and altered kinetics and delayed switching of adult β-globin. This regulation evokes the two human globin switching patterns in the mouse. Both patterns of DNA demethylation and chromatin immunoprecipitation analysis correlated with gene activation and open chromatin. Locus control region (LCR) interactions detected by chromosome conformation capture revealed distinct spatial fetal and adult LCR bigenic subdomains. Since both intact fetal promoters are critical regulators of fetal silencing at the adult stage, we concluded that fetal genes are controlled as a bigenic subdomain rather than a gene-autonomous mechanism. Our study also provides evidence for LCR complex interaction with spatial fetal or adult bigenic functional subdomains as a niche for transcriptional activation and hemoglobin switching.
机译：在发育过程中，人类β-珠蛋白基因座调节经历了两个关键的开关，即胚胎到胎儿和胎儿到成人的血红蛋白开关。为了确定胎儿 A γ-球蛋白启动子在转换中的作用，生产了人类β-球蛋白-YAC转基因小鼠，其中 A γ-球蛋白启动子被红系取代胆色素原脱氨酶（PBGD）启动子（PBGD A γ-YAC）。阶段无关的PBGD A γ-球蛋白的激活在胎儿和成年期显着刺激了天然的 G γ-球蛋白的表达，从而确定了胎儿基因对或双基因合作机制。这种受损的胎儿沉默严重抑制了PBGD A γ-YAC小鼠从胎儿到新生阶段的δ-和β-珠蛋白表达，并改变了动力学，并延迟了成年β-珠蛋白的转换。这种调节在小鼠中引起了两种人类球蛋白的转换模式。 DNA脱甲基和染色质免疫沉淀分析的两种模式均与基因激活和染色质开放相关。通过染色体构象捕获检测到的基因座控制区（LCR）相互作用揭示了独特的空间胎儿和成人LCR双基因亚结构域。由于两个完整的胎儿启动子在成年阶段都是胎儿沉默的关键调控因子，因此我们得出结论，胎儿基因被控制为双基因亚结构域，而不是基因自主机制。我们的研究还提供了LCR与空间胎儿或成年双基因功能亚域相互作用的证据，以此作为转录激活和血红蛋白转换的利基。

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