Inducible Disruption of Genes Results in Myeloid Malignancy, Readthrough Transcription, and a Heterochromatin-to-euchromatin Switch

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2023 Jul 5

PMID 37406303

Authors

Hiroshi Yuita

Isaac F Lopez-Moyado

Hyeongmin Jeong

Arthur Xiuyuan Cheng

James Scott-Browne

Jungeun An

Toshinori Nakayama

Atsushi Onodera

Myunggon Ko

Anjana Rao

Affiliations

Soon will be listed here.

Abstract

The three mammalian TET dioxygenases oxidize the methyl group of 5-methylcytosine 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 genes in the mouse genome. () mice succumbed to acute myeloid leukemia (AML) by 4 to 5 wk. Single-cell RNA sequencing of bone marrow cells revealed the appearance of new myeloid cell populations characterized by a striking increase in expression of all members of the gene cluster on mouse chromosome 16. In patients with AML, high gene expression correlates with poor clinical outcomes. Increased expression of the clustered genes was associated with a heterochromatin-to-euchromatin compartment switch with readthrough transcription downstream of the clustered 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.

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