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Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch

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Title
Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch
Author(s)
Yuita, H.; López-Moyado, I.F.; Jeong, H.; Cheng, A.X.; Scott-Browne, J.; An, J.; Nakayama, T.; Onodera, A.; Myunggon Ko; Rao, A.
Publication Date
2023-02
Journal
Proceedings of the National Academy of Sciences of the United States of America, v.120, no.6
Publisher
National Academy of Sciences
Abstract
The three mammalian TET dioxygenases oxidize the methyl group of 5-methylcy-tosine in DNA, and the oxidized methylcytosines are essential intermediates in all known pathways of DNA demethylation. To define the in vivo consequences of complete TET deficiency, we inducibly deleted all three Tet genes in the mouse genome. Tet1/2/3-inducible TKO (iTKO) mice succumbed to acute myeloid leukemia (AML) by 4 to 5 wk. Single-cell RNA sequencing of Tet iTKO bone marrow cells revealed the appearance of new myeloid cell populations characterized by a striking increase in expression of all members of the stefin/cystatin gene cluster on mouse chromosome 16. In patients with AML, high stefin/cystatin gene expression correlates with poor clinical outcomes. Increased expression of the clustered stefin/cystatin genes was associated with a heterochromatin-to-euchromatin compartment switch with readthrough transcription downstream of the clustered stefin/cystatin genes as well as other highly expressed genes, but only minor changes in DNA methylation. Our data highlight roles for TET enzymes that are distinct from their established function in DNA demethylation and instead involve increased transcriptional readthrough and changes in three-dimensional genome organization. Copyright © 2023 the Author(s).
URI
https://pr.ibs.re.kr/handle/8788114/13391
DOI
10.1073/pnas.2214824120
ISSN
0027-8424
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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