micro RNAのヒトの発生における役割

2024年ノーベル医学生理学賞は、マイクロRNAの発見者2人Victor AmbrosとGary Ruvkunに授与されました。そもそもmicro RNAとは何でしょうか？比較的最近見つかったものなので、知らない人も多いかもしれません。マイクロRNAは標的となるmRNAに結合して、そのmRNAからの翻訳を抑制します。このような翻訳調節機構はそれまで全く知られていなかったので、非常に新しいものでした。線虫に特有な現象なのではないのかという懐疑的な見方もあったかもしれませんが、その後、実はマイクロRNAによる翻訳調節機構は、ヒトを含む哺乳類にまで共通する、非常に普遍性の高い仕組みだということがわかり、その意義の大きさが認識されるようになったのです。

  1. From Worm Anomaly to Nobel Prize  Oct 21, 2024 https://www.the-scientist.com/from-worm-anomaly-to-nobel-prize-micrornas-show-macro-impact-72260

世界で最初に見つかったマイクロRNAは、線虫のlin-4と呼ばれるものでした。lin-4が抑制するmRNAは、lin-14と呼ばれる遺伝子のmRNAです。ノーベル財団の受賞理由の説明が非常にわかりやすいと思います。

Announcement of the 2024 Nobel Prize in Physiology or Medicine Nobel Prize チャンネル登録者数 63.1万人

  1. https://www.nobelprize.org/prizes/medicine/2024/press-release/

この二人の論文は、Cell誌の同じ号に同時に掲載されました。

  1. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 Rosalind C. Lee ,Rhonda L. Feinbaum and Victor Ambros 　https://www.sciencedirect.com/science/article/pii/009286749390529Y?via%3Dihub
  2. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans  Bruce Wightman, Ilho Ha, Gary Ruvkun Volume 75, Issue 5 , 3 December 1993, Pages 855-862 Cell https://www.sciencedirect.com/science/article/pii/0092867493905304

当初は線虫特有の話かと思われたmicroRNAですが、その後、他の動物種にも広く存在する別のマイクロRNAが線虫で発見されて、突如、細胞生物学のひのき舞台にmicroRNAが出てきたと思います。

  1. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA　Nature volume 408, pages86–89 (2000)　Published: 02 November 2000

 

ヒトのマイクロRNA

  • The chromosome 19 miRNA cluster (C19MC) is the largest human miRNA gene cluster, comprising roughly 8% of all known human miRNA genes, and is exclusively expressed in the placenta and in undifferentiated cells
  • MicroRNAs (miRNAs) are endogenous, 19–24 nucleotide, non-coding RNAs that post-transcriptionally regulate gene expression through sequence-specific base-pairing with target mRNAs.
  • In the human placenta, miRNAs are synthesized and expressed primarily in trophoblasts.
  • This primate-specific miRNA cluster spans ∼100 kb at human chromosome 19q13.41, and spans 46 miRNA genes
  •  In the human placenta, the C19MC cluster is imprinted, and is exclusively expressed from the paternally inherited allele
  • Aberrant expression of C19MC miRNAs is observed in specific human malignancies, where they may contribute to tumor invasiveness (; ).

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The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes　Mol Hum Reprod. 2012 Aug; 18(8): 417–424. Published online 2012 Feb 29. doi: 10.1093/molehr/gas013 PMCID: PMC3389496 PMID: 22383544

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389496/

ヒト胚発生におけるマイクロRNAの役割：栄養膜細胞への分化

This figure summarizes simplistically some of the features of trophoblast fate that are at least partly governed by miRNA expression. Trophoblast cells are represented in blue with a round nucleus. Trophoblasts (in blue) can proliferate (left part of the figure) or differentiate into syncytiotrophoblast (right part of the figure; in this case, nuclei are filled in purple) or into endovascular or interstitial trophoblast in the vascular context of maternal arteries (represented as a cone in the lower part of the figure; in this case the nuclei are represented in light blue). In this latter case, they eventually become enclosed into the arterial wall to become intramural trophoblast along pathways that are still debated as nicely described by Pijnenborg et al. (2006). In the figure, crucial genes for cell cycle, Nodal, Notch, and FGF pathways, ROS production, invasion, and angiogenesis are presented in red. Crucial miRNAs are in blue. Blue arrows represent cell differentiation/proliferation pathways. Black arrows symbolize induction. When black lines are terminated by an orthogonal bar they represent inhibition. In the cases where the relation is not fully demonstrated, dotted arrows are used. It is clear that this vision is far from exhaustive, but attempts to depict current knowledge on the role of miRNA in building placental structure and ensuring efficient vascularization of this organ.

Trophoblasts, invasion, and microRNA Frontiers Frontiers in Genetics November 20134:248 DOI:10.3389/fgene.2013.00248　License　CC BY 3.0

https://www.researchgate.net/figure/This-figure-summarizes-simplistically-some-of-the-features-of-trophoblast-fate-that-are_fig1_259208444

  1. 受精卵から胎盤が生まれる仕組み、東北大学などが解明20229/08ニュース2022年9月8日 国際幹細胞普及機構　https://stemcells.or.jp/baby/　受精卵から胎盤が作られる過程を考えると、受精卵は着床後に将来胎児になる細胞と、胎盤になる細胞、2つのタイプに分かれます。つまり、細胞の「運命決定」がなされます。‥　つまり、運命決定とは大まかに言えば、ES細胞と栄養膜幹細胞のどちらになるか、ということなのです。‥　C19MCは、ヒトを含む霊長類のDNAにのみ存在します。発現する場所はほぼ胎盤に限られますが、精巣、胚性幹細胞、一部の腫瘍、そして栄養細胞由来の小胞でも発現しています。‥　人工的にES細胞でC19MC遺伝子の作用を強めてみました。その結果、ES細胞は、栄養膜幹細胞に変化
  2. The microRNA cluster C19MC confers differentiation potential into trophoblast lineages upon human pluripotent stem cells　Nature Communications volume 13, Article number: 3071 (2022)　Published: 02 June 2022　https://www.nature.com/articles/s41467-022-30775-w
  3. Chromosome 19 microRNA cluster enhances cell reprogramming by inhibiting epithelial-to-mesenchymal transition　Scientific Reports volume 10, Article number: 3029 (2020)　Published: 20 February 2020 https://www.nature.com/articles/s41598-020-59812-8
  4. Selective activation of miRNAs of the primate-specific chromosome 19 miRNA cluster (C19MC) in cancer and stem cells and possible contribution to regulation of apoptosis Phan Nguyen Nhi Nguyen, Chiu-Jung Huang, Shigeki Sugii, Soon Keng Cheong & Kong Bung Choo Journal of Biomedical Science volume 24, Article number: 20 (2017)　https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-017-0326-z
  5. C19MC MicroRNAs Regulate the Migration of Human Trophoblasts　Endocrinology. 2014 Dec; 155(12): 4975–4985. Published online 2014 Sep 11. doi: 10.1210/en.2014-1501 PMCID: PMC4239420 PMID: 25211593
  6. The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes　Mol Hum Reprod. 2012 Aug; 18(8): 417–424. Published online 2012 Feb 29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389496/

胎盤とマイクロRNA

Placental trophoblast cell-derived exosomal microRNA-1290 promotes the interaction between endometrium and embryo by targeting LHX6　Nucleic Acids Volume 26 , 3 December 2021, Pages 760-772

https://www.sciencedirect.com/science/article/pii/S2162253121002389

  1. Imprinted MicroRNA Gene Clusters in the Evolution, Development, and Functions of Mammalian Placenta　REVIEW article Front. Genet., 18 January 2019 Sec. RNA Volume 9 – 2018 | https://doi.org/10.3389/fgene.2018.00706 https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00706/full