表观遗传学在复发性流产中的研究进展

doi:10.12280/gjszjk.20200493

摘要/Abstract

摘要：

复发性流产（recurrent spontaneous abortion,RSA）是一种常见的病理性妊娠,其发病机制复杂,常涉及遗传、内分泌、免疫系统、生殖结构异常和环境等多方面因素,人群发病率约为2%~5%。目前仍有约50%患者的发病机制尚不明确,因此,探索新的RSA的生理病理机制迫在眉睫。研究表明表观遗传学通过激活或抑制决定细胞分化、增殖和凋亡等基本生命过程的关键基因表达,在RSA的发生、发展中发挥着重要作用,这些基因不仅有望成为诊断RSA的潜在生物标志物,也可能是治疗RSA的新靶点,具有极其重要的临床意义。从表观遗传学角度,综述DNA 甲基化、组蛋白修饰和非编码 RNA调控等表观遗传调控在RSA中的研究进展,以期为RSA的诊疗提供新的视角。

关键词: 流产, 习惯性, 后成说, 遗传, DNA甲基化, 组蛋白密码, RNA, 未翻译

Abstract:

Recurrent spontaneous abortion (RSA) is a kind of common pathological pregnancy. The pathogenesis of RSA is complex, involving in many factors such as heredity, endocrine, immune system, abnormal reproductive structure, environment, and so on. Although the incidence of RSA is about 2%-5%, the etiology and pathogenesis of about 50% cases remain unclear. A growing number of studies have shown that epigenetics plays a subtle role in the occurrence and development of RSA through activating or inhibiting the expression of key genes that determine cell differentiation, proliferation and apoptosis. These genes are expected to become potential biomarkers for the diagnosis of RSA, but also new targets for the treatment of RSA. From the perspective of epigenetics, we review the research progress of DNA methylation, histone modification and noncoding RNA regulation in RSA, so as to provide a new perspective for the diagnosis and treatment of RSA.

Key words: Abortion, habitual, Epigenesis, genetic, DNA methylation, Histone modification, RNA, non-coding

朱璟希, 李红. 表观遗传学在复发性流产中的研究进展[J]. 国际生殖健康/计划生育, 2021, 40(1): 69-73.

ZHU Jing-xi, LI Hong. Research Progress of Epigenetics in Recurrent Spontaneous Abortion[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(1): 69-73.

参考文献 36

[1]	中华医学会妇产科学分会产科学组. 复发性流产诊治的专家共识[J]. 中华妇产科杂志, 2016,51(1):3-9. doi: 10.3760/cma.j.issn.0529-567x.2016.01.002.
[2]	El Hachem H, Crepaux V, May-Panloup P, et al. Recurrent pregnancy loss: current perspectives[J]. Int J Womens Health, 2017,9:331-345. doi: 10.2147/IJWH.S100817.
[3]	Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org. Definitions of infertility and recurrent pregnancy loss: a committee opinion[J]. Fertil Steril, 2020,113(3):533-535. doi: 10.1016/j.fertnstert.2019.11.025.
[4]	Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes,evaluation and management[J]. Postgrad Med J, 2015,91(1073):151-162. doi: 10.1136/postgradmedj-2014-132672.
[5]	Nilsson EE, Sadler-Riggleman I, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of disease[J]. Environ Epigenet, 2018 Jul 17;4(2):dvy016. doi: 10.1093/eep/dvy016.
[6]	Lesch BJ, Tothova Z, Morgan EA, et al. Intergenerational epigenetic inheritance of cancer susceptibility in mammals[J]. Elife, 2019,8:e39380. doi: 10.7554/eLife.39380.
[7]	Michalak EM, Burr ML, Bannister AJ, et al. The roles of DNA,RNA and histone methylation in ageing and cancer[J]. Nat Rev Mol Cell Biol, 2019,20(10):573-589. doi: 10.1038/s41580-019-0143-1.
[8]	Law PP, Holland ML. DNA methylation at the crossroads of gene and environment interactions[J]. Essays Biochem, 2019,63(6):717-726. doi: 10.1042/EBC20190031.
[9]	Kazmi N, Sharp GC, Reese SE, et al. Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns[J]. Hypertension, 2019,74(2):375-383. doi: 10.1161/HYPERTENSIONAHA.119.12634.
[10]	Zhu L, Liu M, Zhang S, et al. Foxp3 TSDR Hypermethylation Is Correlated with Decreased Tregs in Patients with Unexplained Recurrent Spontaneous Abortion[J]. Reprod Sci, 2020 Aug 24. doi: 10.1007/s43032-020-00299-z. Epub ahead of print.
[11]	Pi L, Zhang Z, Gu Y, et al. DNA methylation profiling in recurrent miscarriage[J]. PeerJ, 2020,8:e8196. doi: 10.7717/peerj.8196.
[12]	Hanna CW, McFadden DE, Robinson WP. DNA methylation profiling of placental villi from karyotypically normal miscarriage and recurrent miscarriage[J]. Am J Pathol, 2013,182(6):2276-2284. doi: 10.1016/j.ajpath.2013.02.021.
[13]	Yu M, Du G, Xu Q, et al. Integrated analysis of DNA methylome and transcriptome identified CREB5 as a novel risk gene contributing to recurrent pregnancy loss[J]. EBioMedicine, 2018,35:334-344. doi: 10.1016/j.ebiom.2018.07.042.
[14]	李静, 于学文, 杨洋, 等. 不明原因复发性流产患者绒毛组织中DNA低甲基化及机制[J]. 细胞与分子免疫学杂志, 2019,35(4):351-356. doi: 10.13423/j.cnki.cjcmi.008811.
[15]	Barišić A, Pereza N, Hodžić A, et al. A Single Nucleotide Polymorphism of DNA methyltransferase 3B gene is a risk factor for recurrent spontaneous abortion[J]. Am J Reprod Immunol, 2017,78(6). doi: 10.1111/aji.12765.
[16]	Mishra J, Talwar S, Kaur L, et al. Differential global and MTHFR gene specific methylation patterns in preeclampsia and recurrent miscarriages: A case-control study from North India[J]. Gene, 2019,704:68-73. doi: 10.1016/j.gene.2019.04.036.
[17]	Rotondo JC, Bosi S, Bazzan E, et al. Methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples of infertile couples correlates with recurrent spontaneous abortion[J]. Hum Reprod, 2012,27(12):3632-3638. doi: 10.1093/humrep/des319.
[18]	Traube FR, Carell T. The chemistries and consequences of DNA and RNA methylation and demethylation[J]. RNA Biol, 2017,14(9):1099-1107. doi: 10.1080/15476286.2017.1318241.
[19]	Yang Y, Hsu PJ, Chen YS, et al. Dynamic transcriptomic m6A decoration: writers,erasers,readers and functions in RNA metabolism[J]. Cell Res, 2018,28(6):616-624. doi: 10.1038/s41422-018-0040-8.
[20]	Huang H, Weng H, Chen J. The Biogenesis and Precise Control of RNA m6A Methylation[J]. Trends Genet, 2020,36(1):44-52. doi: 10.1016/j.tig.2019.10.011.
[21]	Kasowitz SD, Ma J, Anderson SJ, et al. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development[J]. PLoS Genet, 2018,14(5):e1007412. doi: 10.1371/journal.pgen.1007412.
[22]	Roundtree IA, Evans ME, Pan T, et al. Dynamic RNA Modifications in Gene Expression Regulation[J]. Cell, 2017,169(7):1187-1200. doi: 10.1016/j.cell.2017.05.045.
[23]	Li XC, Jin F, Wang BY, et al. The m6A demethylase ALKBH5 controls trophoblast invasion at the maternal-fetal interface by regulating the stability of CYR61 mRNA[J]. Theranostics, 2019,9(13):3853-3865. doi: 10.7150/thno.31868.
[24]	Daskalaki MG, Tsatsanis C, Kampranis SC. Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses[J]. J Cell Physiol, 2018,233(9):6495-6507. doi: 10.1002/jcp.26497.
[25]	Demetriadou C, Kirmizis A. Histone Acetyltransferases in Cancer: Guardians or Hazards?[J]. Crit Rev Oncog, 2017,22(3/4):195-218. doi: 10.1615/CritRevOncog.2017024506.
[26]	Fatima N, Ahmed SH, Salhan S, et al. Study of methyl transferase (G9aMT) and methylated histone (H3-K9) expressions in unexplained recurrent spontaneous abortion (URSA) and normal early pregnancy[J]. Mol Hum Reprod, 2011,17(11):693-701. doi: 10.1093/molehr/gar038.
[27]	Mohanty G, Swain N, Goswami C, et al. Histone retention,protein carbonylation,and lipid peroxidation in spermatozoa: Possible role in recurrent pregnancy loss[J]. Syst Biol Reprod Med, 2016,62(3):201-212. doi: 10.3109/19396368.2016.1148798.
[28]	Wang J, Yang J, Yan Y, et al. Effect of adoptive transfer of CD4+CD25+Foxp3+ Treg induced by trichostatin A on the prevention of spontaneous abortion[J]. J Reprod Immunol, 2019,131:30-35. doi: 10.1016/j.jri.2018.12.002.
[29]	谭璐媛, 王妍, 钟文静, 等. 非编码RNA作为疾病诊断标志物[J]. 生命科学, 2018,30(2):204-212. doi: 10.13376/j.cbls/2018027.
[30]	Li D, Li J, Jia B, et al. Genome-wide identification of microRNAs in decidual natural killer cells from patients with unexplained recurrent spontaneous abortion[J]. Am J Reprod Immunol, 2018,80(5):e13052. doi: 10.1111/aji.13052.
[31]	Wang X, Zhang L, Guan C, et al. The polymorphism of rs11614913 T/T in pri-miR-196a-2 alters the miRNA expression and associates with recurrent spontaneous abortion in a Han-Chinese population[J]. Am J Transl Res, 2020,12(5):1928-1941.
[32]	Wu T, Du Y. LncRNAs: From Basic Research to Medical Application[J]. Int J Biol Sci, 2017,13(3):295-307. doi: 10.7150/ijbs.16968.
[33]	Wang L, Tang H, Xiong Y, et al. Differential expression profile of long noncoding RNAs in human chorionic villi of early recurrent miscarriage[J]. Clin Chim Acta, 2017,464:17-23. doi: 10.1016/j.cca.2016.11.001.
[34]	Tian FJ, He XY, Wang J, et al. Elevated Tristetraprolin Impairs Trophoblast Invasion in Women with Recurrent Miscarriage by Destabilization of HOTAIR[J]. Mol Ther Nucleic Acids, 2018,12:600-609. doi: 10.1016/j.omtn.2018.07.001.
[35]	Lei K, Bai H, Wei Z, et al. The mechanism and function of circular RNAs in human diseases[J]. Exp Cell Res, 2018,368(2):147-158. doi: 10.1016/j.yexcr.2018.05.002.
[36]	Qian Y, Wang X, Ruan H, et al. Circular RNAs expressed in chorionic villi are probably involved in the occurrence of recurrent spontaneous abortion[J]. Biomedecine Pharmacotherapie, 2017,88:1154-1162.