CoChat
Sign Up
Cited by 374

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity

Liu, Jiadong, Gao, Mingwei, He, Jiangping, Wu, Kaixin, Lin, Siyuan, Jin, Lingmei, Chen, Yaping, Liu, He, Shi, Junjie, Wang, Xiwei, Chang, Lei, Lin, Yingying, Zhao, Yu-Li, Zhang, Xiaofei, Zhang, Man, Luo, Guan-Zheng, Wu, Guangming, Pei, Duanqing, Wang, Jie, Bao, Xichen, Chen, Jiekai·2021·Nature
DOI 10.1038/s41586-021-03313-9
Open this paper in CoChat — free account

Abstract

The RNA modification N 6 -methyladenosine (m 6 A) has critical roles in many biological processes 1,2 . However, the function of m 6 A in the early phase of mammalian development remains poorly understood. Here we show that the m 6 A reader YT521-B homology-domain-containing protein 1 (YTHDC1) is required for the maintenance of mouse embryonic stem (ES) cells in an m 6 A-dependent manner, and that its deletion initiates cellular reprogramming to a 2C-like state. Mechanistically, YTHDC1 binds to the transcripts of retrotransposons (such as intracisternal A particles, ERVK and LINE1) in mouse ES cells and its depletion results in the reactivation of these silenced retrotransposons, accompanied by a global decrease in SETDB1-mediated trimethylation at lysine 9 of histone H3 (H3K9me3). We further demonstrate that YTHDC1 and its target m 6 A RNAs act upstream of SETDB1 to repress retrotransposons and Dux, the master inducer of the two-cell stage (2C)-like program. This study reveals an essential role for m 6 A RNA and YTHDC1 in chromatin modification and retrotransposon repression.

Overview

Integrity signals

Registry

Crossref · 10.1038/s41586-021-03313-9

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 5 references

Research works printed but not linked: 48

  1. Fu, Y., Dominissini, D., Rechavi, G. & He, C. Gene expression regulation mediated through reversible m6A RNA methylation. Nat. Rev. Genet. 15, 293–306 (2014). · DOI
  2. Yang, Y., Hsu, P. J., Chen, Y. S. & Yang, Y. G. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 28, 616–624 (2018). · DOI
  3. Liu, J. et al. YTHDF2/3 are required for somatic reprogramming through different RNA deadenylation pathways. Cell Rep. 32, 108120 (2020). · DOI
  4. Luo, S. & Tong, L. Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain. Proc. Natl Acad. Sci. USA 111, 13834–13839 (2014). · DOI
  5. Xu, C. et al. Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat. Chem. Biol. 10, 927–929 (2014). · DOI
  6. Kasowitz, S. D. et al. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet. 14, e1007412 (2018). · DOI
  7. Geula, S. et al. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 347, 1002–1006 (2015). · DOI
  8. Shi, H. et al. m6A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563, 249–253 (2018). · DOI · Paper page
  9. Ivanova, I. et al. The RNA m6A reader YTHDF2 is essential for the post-transcriptional regulation of the maternal transcriptome and oocyte competence. Mol. Cell 67, 1059–1067 (2017). · DOI
  10. Hsu, P. J. et al. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 27, 1115–1127 (2017). · DOI
  11. Zhang, Y. et al. RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation. Proc. Natl Acad. Sci. USA 116, 976–981 (2019). · DOI
  12. Wu, Y. et al. Nuclear exosome targeting complex core factor Zcchc8 regulates the degradation of LINE1 RNA in early embryos and embryonic stem cells. Cell Rep. 29, 2461–2472 (2019). · DOI
  13. Liu, J. et al. N6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science 367, 580–586 (2020). · DOI · Paper page
  14. Macfarlan, T. S. et al. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature 487, 57–63 (2012). · DOI · Paper page
  15. Hendrickson, P. G. et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat. Genet. 49, 925–934 (2017). · DOI
  16. Genet, M. & Torres-Padilla, M. E. The molecular and cellular features of 2-cell-like cells: a reference guide. Development 147, dev189688 (2020). · DOI
  17. Wu, K. et al. SETDB1-mediated cell fate transition between 2C-like and pluripotent states. Cell Rep. 30, 25–36 (2020). · DOI
  18. Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014). · DOI
  19. Chelmicki, T. et al. m6A RNA methylation regulates the fate of endogenous retroviruses. Nature https://doi.org/10.1038/s41586-020-03135-1 (2021). · DOI
  20. Jachowicz, J. W. et al. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat. Genet. 49, 1502–1510 (2017). · DOI
  21. Percharde, M. et al. A LINE1-nucleolin partnership regulates early development and ESC identity. Cell 174, 391–405 (2018). · DOI
  22. Matsui, T. et al. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464, 927–931 (2010). · DOI
  23. Li, X. et al. GRID-seq reveals the global RNA-chromatin interactome. Nat. Biotechnol. 35, 940–950 (2017). · DOI
  24. Iturbide, A. & Torres-Padilla, M. E. A cell in hand is worth two in the embryo: recent advances in 2-cell like cell reprogramming. Curr. Opin. Genet. Dev. 64, 26–30 (2020). · DOI
  25. Chen, J. et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat. Genet. 45, 34–42 (2013). · DOI · Paper page
  26. Moazed, D. Small RNAs in transcriptional gene silencing and genome defence. Nature 457, 413–420 (2009). · DOI
  27. Zofall, M. et al. RNA elimination machinery targeting meiotic mRNAs promotes facultative heterochromatin formation. Science 335, 96–100 (2012). · DOI
  28. Wang, C. et al. A novel RNA-binding mode of the YTH domain reveals the mechanism for recognition of determinant of selective removal by Mmi1. Nucleic Acids Res. 44, 969–982 (2016). · DOI
  29. Chen, Z. & Zhang, Y. Loss of DUX causes minor defects in zygotic genome activation and is compatible with mouse development. Nat. Genet. 51, 947–951 (2019). · DOI
  30. Summers, M. C., McGinnis, L. K., Lawitts, J. A., Raffin, M. & Biggers, J. D. IVF of mouse ova in a simplex optimized medium supplemented with amino acids. Hum. Reprod. 15, 1791–1801 (2000). · DOI
  31. Wu, G. et al. Establishment of totipotency does not depend on Oct4A. Nat. Cell Biol. 15, 1089–1097 (2013). · DOI
  32. He, J. et al. Transposable elements are regulated by context-specific patterns of chromatin marks in mouse embryonic stem cells. Nat. Commun. 10, 34 (2019). · DOI
  33. Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011). · DOI · Paper page
  34. Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012). · DOI · Paper page
  35. Jin, Y., Tam, O. H., Paniagua, E. & Hammell, M. TEtranscripts: a package for including transposable elements in differential expression analysis of RNA-seq datasets. Bioinformatics 31, 3593–3599 (2015). · DOI
  36. Hasson, D. et al. The octamer is the major form of CENP-A nucleosomes at human centromeres. Nat. Struct. Mol. Biol. 20, 687–695 (2013). · DOI
  37. Gu, J. et al. GoldCLIP: Gel-omitted Ligation-dependent CLIP. Genomics Proteomics Bioinformatics 16, 136–143 (2018). · DOI
  38. Chu, C., Qu, K., Zhong, F. L., Artandi, S. E. & Chang, H. Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA–chromatin interactions. Mol. Cell 44, 667–678 (2011). · DOI
  39. Fuchs, G. et al. 4sUDRB-seq: measuring genomewide transcriptional elongation rates and initiation frequencies within cells. Genome Biol. 15, R69 (2014). · DOI · Paper page
  40. Feng, J., Liu, T., Qin, B., Zhang, Y. & Liu, X. S. Identifying ChIP-seq enrichment using MACS. Nat. Protocols 7, 1728–1740 (2012). · DOI
  41. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010). · DOI · Paper page
  42. Ramírez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44 (W1), W160–W165 (2016). · DOI · Paper page
  43. Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011). · DOI · Paper page
  44. Kim, D., Paggi, J. M., Park, C., Bennett, C. & Salzberg, S. L. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat. Biotechnol. 37, 907–915 (2019). · DOI · Paper page
  45. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012). · DOI · Paper page
  46. Kumar, V. et al. Uniform, optimal signal processing of mapped deep-sequencing data. Nat. Biotechnol. 31, 615–622 (2013). · DOI
  47. Ng, R. K. et al. Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat. Cell Biol. 10, 1280–1290 (2008). · DOI
  48. Latos, P. A. & Hemberger, M. From the stem of the placental tree: trophoblast stem cells and their progeny. Development 143, 3650–3660 (2016). · DOI

Cited by

See all 374

Metadata

Authors
Liu, J., Gao, M., He, J., Wu, K., Lin, S., Jin, L., Chen, Y., Liu, H., Shi, J., Wang, X., Chang, L., Lin, Y., Zhao, Y.-L., Zhang, X., Zhang, M., Luo, G.-Z., Wu, G., Pei, D., Wang, J., Bao, X., & Chen, J.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-03-03
Volume
591
Issue
7849
Pages
322-326
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/s41586-021-03313-9
Cited by
374
References
5
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity. https://app.cochat.ai/papers/10.1038/s41586-021-03313-9
The paper
Liu, J., Gao, M., He, J., Wu, K., Lin, S., Jin, L., Chen, Y., Liu, H., Shi, J., Wang, X., Chang, L., Lin, Y., Zhao, Y.-L., Zhang, X., Zhang, M., Luo, G.-Z., Wu, G., Pei, D., Wang, J., . . . Chen, J. (2021). The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity. Nature. https://doi.org/10.1038/s41586-021-03313-9