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Context-dependent functional compensation between Ythdf m<sup>6</sup>A reader proteins.

Lior Lasman, Vladislav Krupalnik, Sergey Viukov, Nofar Mor, Alejandro Aguilera-Castrejon, Dan Schneir, Jonathan Bayerl, Orel Mizrahi, Shani Peles, Shadi Tawil, Shashank Sathe, Aharon Nachshon, Tom Shani, Mirie Zerbib, Itay Kilimnik, Stefan Aigner, Archana Shankar, Jasmine R Mueller, Schraga Schwartz, Noam Stern-Ginossar, Gene W Yeo, Shay Geula, Noa Novershtern, Jacob H Hanna

Genes & development · 2020 · Vol. 34 (19-20) · pp. 1373-1391

PubMed ↗ DOI ↗ PMC full text ↗

Abstract

The N6-methyladenosine (m<sup>6</sup>A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins consists of three homologous m<sup>6</sup>A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer, each of the Ythdf readers, and the three readers together (triple-KO). We then estimated the effect in vivo in mouse gametogenesis, postnatal viability, and in vitro in mouse embryonic stem cells (mESCs). In gametogenesis, <i>Mettl3-KO</i> severity is increased as the deletion occurs earlier in the process, and Ythdf2 has a dominant role that cannot be compensated by Ythdf1 or Ythdf3, due to differences in readers' expression pattern across different cell types, both in quantity and in spatial location. Knocking out the three readers together and systematically testing viable offspring genotypes revealed a redundancy in the readers' role during early development that is <i>Ythdf1/2/3</i> gene dosage-dependent. Finally, in mESCs there is compensation between the three Ythdf reader proteins, since the resistance to differentiate and the significant effect on mRNA decay occur only in the triple-KO cells and not in the single KOs. Thus, we suggest a new model for the Ythdf readers function, in which there is profound dosage-dependent redundancy when all three readers are equivalently coexpressed in the same cell types.

Linked datasets 5

GSE148039 GSE · via ncbi_elink
GEO ↗

Ythdf m6A readers compensate each other in a context dependent manner

Mus musculus

GSE147849 GSE · via ncbi_elink
GEO ↗

Ythdf m6A readers compensate each other in a context dependent manner [RNA-seq]

36 data files
FileTypeSize
SRR11459699_GSM4447050 RNA-Seq 2.8 GB
SRR11459700_GSM4447051 RNA-Seq 3.0 GB
SRR11459701_GSM4447052 RNA-Seq 2.4 GB
SRR11459702_GSM4447053 RNA-Seq 2.4 GB
SRR11459703_GSM4447054 RNA-Seq 1.9 GB
SRR11459704_GSM4447055 RNA-Seq 2.3 GB
SRR11459705_GSM4447056 RNA-Seq 1.4 GB
SRR11459706_GSM4447057 RNA-Seq 1.9 GB
SRR11459707_GSM4447058 RNA-Seq 1.6 GB
SRR11459708_GSM4447059 RNA-Seq 1.8 GB
SRR11459709_GSM4447060 RNA-Seq 1.3 GB
SRR11459710_GSM4447061 RNA-Seq 2.1 GB
SRR11459711_GSM4447062 RNA-Seq 1.5 GB
SRR11459712_GSM4447063 RNA-Seq 1.4 GB
SRR11459713_GSM4447064 RNA-Seq 841.0 MB
SRR11459714_GSM4447065 RNA-Seq 1.3 GB
SRR11459715_GSM4447066 RNA-Seq 796.0 MB
SRR11459716_GSM4447067 RNA-Seq 1.1 GB
SRR11459717_GSM4447068 RNA-Seq 970.0 MB
SRR11459718_GSM4447069 RNA-Seq 1.4 GB
SRR11459719_GSM4447070 RNA-Seq 1.4 GB
SRR11459720_GSM4447071 RNA-Seq 2.1 GB
SRR11459721_GSM4447072 RNA-Seq 1.1 GB
SRR11459722_GSM4447073 RNA-Seq 1.9 GB
SRR11459723_GSM4447074 RNA-Seq 472.0 MB
SRR11459724_GSM4447074 RNA-Seq 483.0 MB
SRR11459725_GSM4447074 RNA-Seq 488.0 MB
SRR11459726_GSM4447074 RNA-Seq 481.0 MB
SRR11459727_GSM4447075 RNA-Seq 547.0 MB
SRR11459728_GSM4447075 RNA-Seq 565.0 MB
SRR11459729_GSM4447075 RNA-Seq 572.0 MB
SRR11459730_GSM4447075 RNA-Seq 562.0 MB
SRR11459731_GSM4447076 RNA-Seq 691.0 MB
SRR11459732_GSM4447076 RNA-Seq 711.0 MB
SRR11459733_GSM4447076 RNA-Seq 724.0 MB
SRR11459734_GSM4447076 RNA-Seq 709.0 MB
GSE148038 GSE · via ncbi_elink
GEO ↗

Ythdf m6A readers compensate each other in a context dependent manner [3'UTR RNA-seq]

50 data files
FileTypeSize
SRR11475971_GSM4452888 RNA-Seq 55.0 MB
SRR11475972_GSM4452889 RNA-Seq 42.0 MB
SRR11475973_GSM4452890 RNA-Seq 41.0 MB
SRR11475974_GSM4452891 RNA-Seq 32.0 MB
SRR11475975_GSM4452892 RNA-Seq 35.0 MB
SRR11475976_GSM4452893 RNA-Seq 41.0 MB
SRR11475977_GSM4452894 RNA-Seq 41.0 MB
SRR11475978_GSM4452895 RNA-Seq 59.0 MB
SRR11475979_GSM4452896 RNA-Seq 48.0 MB
SRR11475980_GSM4452897 RNA-Seq 43.0 MB
SRR11475981_GSM4452898 RNA-Seq 33.0 MB
SRR11475982_GSM4452899 RNA-Seq 29.0 MB
SRR11475983_GSM4452900 RNA-Seq 77.0 MB
SRR11475984_GSM4452901 RNA-Seq 51.0 MB
SRR11475985_GSM4452902 RNA-Seq 46.0 MB
SRR11475986_GSM4452903 RNA-Seq 39.0 MB
SRR11475987_GSM4452904 RNA-Seq 38.0 MB
SRR11475988_GSM4452905 RNA-Seq 48.0 MB
SRR11475989_GSM4452906 RNA-Seq 54.0 MB
SRR11475990_GSM4452907 RNA-Seq 51.0 MB
SRR11475991_GSM4452908 RNA-Seq 72.0 MB
SRR11475992_GSM4452909 RNA-Seq 59.0 MB
SRR11475993_GSM4452910 RNA-Seq 48.0 MB
SRR11475994_GSM4452911 RNA-Seq 43.0 MB
SRR11475995_GSM4452912 RNA-Seq 37.0 MB
SRR11475996_GSM4452913 RNA-Seq 77.0 MB
SRR11475997_GSM4452914 RNA-Seq 66.0 MB
SRR11475998_GSM4452915 RNA-Seq 51.0 MB
SRR11475999_GSM4452916 RNA-Seq 43.0 MB
SRR11476000_GSM4452917 RNA-Seq 42.0 MB
SRR11476001_GSM4452918 RNA-Seq 58.0 MB
SRR11476002_GSM4452919 RNA-Seq 65.0 MB
SRR11476003_GSM4452920 RNA-Seq 45.0 MB
SRR11476004_GSM4452921 RNA-Seq 45.0 MB
SRR11476005_GSM4452922 RNA-Seq 41.0 MB
SRR11476006_GSM4452923 RNA-Seq 64.0 MB
SRR11476007_GSM4452924 RNA-Seq 68.0 MB
SRR11476008_GSM4452925 RNA-Seq 48.0 MB
SRR11476009_GSM4452926 RNA-Seq 43.0 MB
SRR11476010_GSM4452927 RNA-Seq 39.0 MB
SRR11476011_GSM4452928 RNA-Seq 54.0 MB
SRR11476012_GSM4452929 RNA-Seq 63.0 MB
SRR11476013_GSM4452930 RNA-Seq 52.0 MB
SRR11476014_GSM4452931 RNA-Seq 50.0 MB
SRR11476015_GSM4452932 RNA-Seq 51.0 MB
SRR11476016_GSM4452933 RNA-Seq 61.0 MB
SRR11476017_GSM4452934 RNA-Seq 70.0 MB
SRR11476018_GSM4452935 RNA-Seq 59.0 MB
SRR11476019_GSM4452936 RNA-Seq 52.0 MB
SRR11476020_GSM4452937 RNA-Seq 58.0 MB
GSE148536 GSE · via ncbi_elink
GEO ↗

Ythdf m6A readers compensate each other in a context dependent manner [Ribo-seq]

12 data files
FileTypeSize
SRR11539365_GSM4473269 OTHER 1.0 GB
SRR11539366_GSM4473270 OTHER 670.0 MB
SRR11539367_GSM4473271 OTHER 1.1 GB
SRR11539368_GSM4473272 OTHER 963.0 MB
SRR11539369_GSM4473273 OTHER 1.0 GB
SRR11539370_GSM4473274 OTHER 695.0 MB
SRR11539371_GSM4473275 OTHER 788.0 MB
SRR11539372_GSM4473276 OTHER 1001.0 MB
SRR11539373_GSM4473277 OTHER 896.0 MB
SRR11539374_GSM4473278 OTHER 677.0 MB
SRR11539375_GSM4473279 OTHER 600.0 MB
SRR11539376_GSM4473280 OTHER 697.0 MB
GSE151788 GSE · via ncbi_elink
GEO ↗

Ythdf m6A readers compensate each other in a context dependent manner [eCLIP]

8 data files
FileTypeSize
SRR11923227_GSM4590952 OTHER 606.0 MB
SRR11923228_GSM4590952 OTHER 672.0 MB
SRR11923229_GSM4590953 OTHER 757.0 MB
SRR11923230_GSM4590953 OTHER 639.0 MB
SRR11923231_GSM4590954 OTHER 870.0 MB
SRR11923232_GSM4590954 OTHER 573.0 MB
SRR11923233_GSM4590955 OTHER 655.0 MB
SRR11923234_GSM4590955 OTHER 546.0 MB

Potentially related datasets 1

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

Accession Source Title
GSE148039 GSE · GEO GEO ↗ Ythdf m6A readers compensate each other in a context dependent manner

Analysis pipelines 5

Pipeline Assay Steps Dataset
GSE147849 RNA-seq Data Processing geo_data_processing RNA-seq 7 GSE147849
GSE148038 RNA-seq Data Processing geo_data_processing RNA-seq 5 GSE148038
GSE148039 Data Processing geo_data_processing — 7 GSE148039
GSE148536 Ribo-seq Data Processing geo_data_processing Ribo-seq 7 GSE148536
GSE151788 eCLIP Data Processing geo_data_processing eCLIP 33 GSE151788
Funding 1 grant
Grant Funder
R01 HG004659 NHGRI NIH HHS (United States)