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浙江大学学报（医学版）
浙江大学学报（医学版）  2020, Vol. 49 Issue (1): 58-70    DOI: 10.3785/j.issn.1008-9292.2020.02.25
专题报道     
铁稳态代谢表观遗传调控机制的研究进展
段玲艳1(),尹香菊2,孟红恩1,方学贤1,闵军霞1,王福俤1,*()
1. 浙江大学医学院, 浙江 杭州 310058
2. 河南理工大学资源环境学院, 河南 焦作 454000
Progress on epigenetic regulation of iron homeostasis
DUAN Lingyan1(),YIN Xiangju2,MENG Hong'en1,FANG Xuexian1,MIN Junxia1,WANG Fudi1,*()
1. School of Medicine, Zhejiang University, Hangzhou 310058, China
2. School of Resources and Environment, Henan Polytechnic University, Jiaozuo 454000, Henan Province, China
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摘要：

铁稳态在机体生长发育和健康维持中发挥重要作用，而机体铁稳态代谢受二价金属离子转运蛋白（DMT1）、转铁蛋白受体1（TFR1）、转铁蛋白受体2（TFR2）、铁外排蛋白（FPN）、铁调素（HAMP）、铁调素调节蛋白（HJV）、铁蛋白重链（Ferritin H）等关键基因精密调控。近年研究报道，DNA甲基化、组蛋白乙酰化和微RNA（miRNA）等表观遗传机制可发挥调控铁稳态的作用。其中，DNA甲基化可通过调控FPN、TFR2、HAMP、HJV和骨形态生成蛋白BMP家族成员6（BMP6）等铁代谢基因启动子区甲基化水平而影响这些基因的表达。此外，组蛋白脱乙酰酶（HDAC）能够通过抑制HAMP基因表达而调控铁代谢；而HDAC抑制剂可促进HAMP基因表达。多个miRNA可靶向DMT1、FPN、TFR1、TFR2和Ferritin H等基因，通过抑制这些铁代谢关键基因的表达而影响机体铁的吸收、转运、储存和利用过程。值得关注的是，表观遗传调控的一些关键酶，如DNA去甲基化酶TET2和组蛋白赖氨酸去甲基酶JmjC KDM需要铁离子才能发挥酶促活性。本文综述了DNA甲基化、组蛋白乙酰化和miRNA等表观遗传机制调控铁稳态代谢的国内外最新研究进展，并针对未来研究方向进行了讨论。
关键词： 铁/代谢;  DNA甲基化;  组蛋白类/蛋白质修饰;  微RNA;  表观遗传;  综述    
Abstract:

Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1(DMT1), transferrin receptor 1(TFR1), transferrin receptor 2(TFR2), ferroportin(FPN), hepcidin(HAMP), hemojuvelin(HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 (BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.
Key words: Iron/metabolism    DNA methylation    Histones/protein modification    MicroRNAs    Epigenetics    Review
收稿日期: 2019-11-19 出版日期: 2020-06-08
CLC:  R333.6  
基金资助: 国家重点研发计划(2018YFA0507800);国家自然科学基金(31930057, 31530034, 31570791)
通讯作者: 王福俤     E-mail: duanlingyan@zju.edu.cn;fwang@zju.edu.cn
作者简介: 段玲艳(1993-), 女, 硕士研究生, 主要从事铁代谢表观遗传学研究; E-mail:duanlingyan@zju.edu.cn; https://orcid.org/0000-0002-5016-7023
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引用本文:

段玲艳,尹香菊,孟红恩,方学贤,闵军霞,王福俤. 铁稳态代谢表观遗传调控机制的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 58-70.

DUAN Lingyan,YIN Xiangju,MENG Hong'en,FANG Xuexian,MIN Junxia,WANG Fudi. Progress on epigenetic regulation of iron homeostasis. J Zhejiang Univ (Med Sci), 2020, 49(1): 58-70.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.02.25    或    http://www.zjujournals.com/med/CN/Y2020/V49/I1/58

图 1  铁稳态代谢和表观遗传调控铁代谢
图 2  铁调素的表观遗传调控
靶点 微RNA 文献
二价金属离子转运蛋白 miR-let-7d、miR-16家族 [81-82]
铁外排蛋白 miR-20a、miR-20b、miR-485-3p [83-85]
转铁蛋白受体1 miR-210、miR-320、miR-152、miR-148a、miR-7-5p、miR-141-3p [86-90]
铁硫簇组装蛋白 miR-210 [91]
转铁蛋白受体2 miR-221 [92]
核转录因子E2相关因子2 miR-144 [93]
铁蛋白重链 miR-200b [94]
铁反应元件结合蛋白2 miR-29家族 [95]
骨形态生成蛋白Ⅰ型受体 miR-130a [96]
铁调素调节蛋白 miR-122 [97]
血色素沉着病蛋白 miR-122 [97]
5-氨基酮戊酸合成酶 miR-218 [98]
γ-珠蛋白 miR-96 [99]
Bach 1(一种编码血红素调节转录抑制因子的基因) miR-let-7、miR-196、miR-27a-5p [100-102]
乳铁蛋白 miR-214 [103]
乳铁蛋白受体 miR-584 [104]
表 1  微RNA调控铁代谢的关键靶点
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