GEO series
TET2 regulates histone H2AK119ub and leukemogenesis through LTR RNA m5C oxidation [seq_DNA-CUTandTag]
GSE241304
Homo sapiens; Mus musculus
Genome binding/occupancy profiling by high throughput sequencing
24 samples
Submitted 2024/07/25
Platform GPL24676Platform GPL24247
Summary
Mutation of TET2 drives myeloid malignancy progression. TET2 deficiency is known to cause a globally opened chromatin and activation of genes contributing to aberrant HSPC self-renewal. We show here that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C), installed by NSUN2, can be recognized by the methyl-CpG-binding domain protein MBD6, which guides deubiquitylation of nearby histone H2AK119ub to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitylation. Thereby, TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription in stem cells. TET2 mutant human leukemia became dependent on this gene activation pathway, with MBD6 silencing selectively inhibits proliferation of TET2 mutant leukemia in vitro and in vivo. Altogether, our findings reveal a previously unknown chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.
Published in
Zou Z, Dou X, Li Y et al.
· Nature 2024
· PMID 39358506
· doi:10.1038/s41586-024-07969-x
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE241304_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 24 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1007667 and SRA study SRP456132. Searching any of these in the dataset finder brings you back here.
Study design
12 conditions, mostly in duplicate
mESC, Tet2 WT, H2AK119ub, CUT&Tag, ×2
mESC, Tet2 KO, H2AK119ub, CUT&Tag, ×2
mESC, Tet2 WT, H3K27me3, CUT&Tag, ×2
mESC, Tet2 KO, H3K27me3, CUT&Tag, ×2
mLK, Tet2 WT, H2AK119ub, CUT&Tag, ×2
mLK, Tet2 KO, H2AK119ub, CUT&Tag, ×2
mLK, Tet2 WT, H3K27me3, CUT&Tag, ×2
mLK, Tet2 KO, H3K27me3, CUT&Tag, ×2
+4 more
Supports a between-group comparison across 24 samples.
12 replicated groups read from 24 sample titles; they account for 24 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM7720826 mESC, Tet2 WT, H2AK119ub, CUT&Tag, rep1
- GSM7720827 mESC, Tet2 WT, H2AK119ub, CUT&Tag, rep2
- GSM7720828 mESC, Tet2 KO, H2AK119ub, CUT&Tag, rep1
- GSM7720829 mESC, Tet2 KO, H2AK119ub, CUT&Tag, rep2
- GSM7720830 mESC, Tet2 WT, H3K27me3, CUT&Tag, rep1
- GSM7720831 mESC, Tet2 WT, H3K27me3, CUT&Tag, rep2
- GSM7720832 mESC, Tet2 KO, H3K27me3, CUT&Tag, rep1
- GSM7720833 mESC, Tet2 KO, H3K27me3, CUT&Tag, rep2
- GSM7720834 mLK, Tet2 WT, H2AK119ub, CUT&Tag, rep1
- GSM7720835 mLK, Tet2 WT, H2AK119ub, CUT&Tag, rep2
- GSM7720836 mLK, Tet2 KO, H2AK119ub, CUT&Tag, rep1
- GSM7720837 mLK, Tet2 KO, H2AK119ub, CUT&Tag, rep2
- GSM7720838 mLK, Tet2 WT, H3K27me3, CUT&Tag, rep1
- GSM7720839 mLK, Tet2 WT, H3K27me3, CUT&Tag, rep2
- GSM7720840 mLK, Tet2 KO, H3K27me3, CUT&Tag, rep1
- GSM7720841 mLK, Tet2 KO, H3K27me3, CUT&Tag, rep2
- GSM7720842 K562, siControl, H2AK119ub, CUT&Tag, rep1
- GSM7720843 K562, siControl, H2AK119ub, CUT&Tag, rep2
- GSM7720844 K562, siMBD6, H2AK119ub, CUT&Tag, rep1
- GSM7720845 K562, siMBD6, H2AK119ub, CUT&Tag, rep2
- GSM7720846 K562, TET2 WT, H2AK119ub, CUT&Tag, rep1
- GSM7720847 K562, TET2 WT, H2AK119ub, CUT&Tag, rep2
- GSM7720848 K562, TET2 KO, H2AK119ub, CUT&Tag, rep1
- GSM7720849 K562, TET2 KO, H2AK119ub, CUT&Tag, rep2
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