Heterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ε-Globin Gene Expression
Heterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ε-Globin Gene Expression
复制标题
异染色质蛋白 1gamma 是人类胚胎珠蛋白基因表达的新型表观遗传抑制因子。
DOI：
10.1074/jbc.m116.768515
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发表时间：
2017-03-24
影响因子：
4.8
通讯作者：
Zhao, Quan
中科院分区：
文献类型：
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作者：
Wang, Yadong;Wang, Ying;Zhao, Quan
在发育过程中血红蛋白的产生受到严格的调节。例如，来自人β-珠蛋白基因座的表达，包括β、δ、γ和γ珠蛋白基因，在胚胎发育期间从β-珠蛋白转换为ε-珠蛋白，然后在出生后从β-珠蛋白转换为β-珠蛋白。人β-珠蛋白在小鼠中的表达已显示出改善由β-珠蛋白突变引起的贫血，包括引起β-地中海贫血和镰状细胞病的那些，提高了β-珠蛋白表达的再激活可用于管理人类中的这些病症的前景。虽然已知人类珠蛋白基因受多种含有催化表观遗传修饰的酶的多蛋白复合物调控，但控制β-珠蛋白基因沉默的确切机制仍然难以捉摸。在这里，我们发现，异染色质蛋白HP 1 γ，一个多功能的染色质和DNA结合蛋白的转录激活和延伸的作用，抑制ε-珠蛋白的表达，通过与组蛋白修饰酶，赖氨酸甲基转移酶SUV 4 - 20 H2。沉默HP 1 γ表达显著降低了抑制性组蛋白标记和组蛋白H3赖氨酸9和H4赖氨酸20的多甲基化，导致ε-珠蛋白基因近端启动子DNA甲基化显著降低，ε-珠蛋白表达大大增加。此外，使用染色质免疫沉淀，我们表明，SUV 4 - 20 h2有利于沉积的HP 1 γ的ε-珠蛋白近端启动子。因此，这些数据表明，HP 1 γ是一种新的epsilon-珠蛋白基因表达的表观遗传阻遏物，并为β-地中海贫血和镰状细胞病的靶向治疗提供了潜在的策略。
Production of hemoglobin during development is tightly regulated. For example, expression from the human beta-globin gene locus, comprising beta, delta, epsilon, and gamma globin genes, switches from beta-globin to epsilon-globin during embryonic development and then from beta-globin to beta-globin after birth. Expression of human beta-globin in mice has been shown to ameliorate anemia caused by beta-globin mutations, including those causing beta-thalassemia and sickle cell disease, raising the prospect that reactivation of beta-globin expression could be used in managing these conditions in humans. Although the human globin genes are known to be regulated by a variety of multiprotein complexes containing enzymes that catalyze epigenetic modifications, the exact mechanisms controlling beta-globin gene silencing remain elusive. Here we found that the heterochromatin protein HP1 gamma, a multifunctional chromatin-and DNA-binding protein with roles in transcriptional activation and elongation, represses epsilon-globin expression by interacting with a histone-modifying enzyme, lysine methyltransferase SUV4-20h2. Silencing of HP1 gamma expression markedly decreased repressive histone marks and the multimethylation of histone H3 lysine 9 and H4 lysine 20, leading to a significant decrease in DNA methylation at the proximal promoter of the epsilon-globin gene and greatly increased epsilon-globin expression. In addition, using chromatin immunoprecipitation, we showed that SUV4-20h2 facilitates the deposition of HP1 gamma on the epsilon-globin-proximal promoter. Thus, these data indicate that HP1 gamma is a novel epigenetic repressor of epsilon-globin gene expression and provide a potential strategy for targeted therapies for beta-thalassemia and sickle cell disease.