Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.
Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.
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DOI：
10.1073/pnas.2214824120
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发表时间：
2023-02-07
影响因子：
11.1
通讯作者：
Rao, Anjana
中科院分区：
文献类型：
--
作者：
Yuita, Hiroshi;Lopez-Moyado, Isaac F.;Jeong, Hyeongmin;Cheng, Arthur Xiuyuan;Scott-Browne, James;An, Jungeun;Nakayama, Toshinori;Onodera, Atsushi;Ko, Myunggon;Rao, Anjana
关键词：
泰特功能丧失与癌症密切相关。我们产生了所有三种泰特基因的可诱导缺失的小鼠模型（泰特iTKO小鼠），以研究泰特酶缺失的体内影响。泰特iTKO小鼠在4至5周内发生快速和致命的骨髓扩增。扩增的骨髓细胞包括新的细胞群，其特征在于小鼠16号染色体上Stefin基因簇的上调，伴随着包含相同区域的异染色质至常染色质的转换。Stefin/半胱氨酸蛋白酶抑制剂基因编码半胱氨酸蛋白酶抑制剂，其尤其抑制组织蛋白酶。我们发现stefin/cystatin基因的高表达与急性髓细胞白血病患者的不良临床结局相关，并讨论了泰特缺乏与基因组结构变化的关系。三种哺乳动物泰特双加氧酶氧化DNA中5-甲基胞嘧啶的甲基，并且氧化的甲基胞嘧啶是所有已知的DNA去甲基化途径中必不可少的中间体。为了确定完全泰特缺乏的体内后果，我们诱导删除了小鼠基因组中的所有三个泰特基因。Tet 1/2/3诱导的TKO（iTKO）小鼠在4至5周死于急性髓性白血病（AML）。泰特iTKO骨髓细胞的单细胞RNA测序揭示了新的髓样细胞群的出现，其特征在于小鼠16号染色体上stefin/半胱氨酸蛋白酶抑制剂基因簇的所有成员的表达显著增加。在AML患者中，stefin/cystatin基因高表达与不良临床结局相关。成簇的stefin/半胱氨酸蛋白酶抑制剂基因的表达增加与异染色质到常染色质区室开关相关，其具有成簇的stefin/半胱氨酸蛋白酶抑制剂基因以及其他高表达基因下游的通读转录，但DNA甲基化仅发生微小变化。我们的数据突出了泰特酶的作用，这些酶与它们在DNA去甲基化中的既定功能不同，而是涉及增加转录通读和三维基因组组织的变化。
TET loss of function is strongly linked to cancer. We generated a mouse model of inducible deletion of all three Tet genes (Tet iTKO mice) to study the in vivo effects of loss of TET enzymes. Tet iTKO mice develop rapid and fatal myeloid expansion within 4 to 5 wk. The expanded myeloid cells include new cell populations characterized by upregulation of the Stefin gene cluster on mouse chromosome 16, accompanied by a heterochromatin-to-euchromatin switch encompassing the same region. Stefin/cystatin genes encode cysteine protease inhibitors that inhibit cathepsin proteases among others. We show that high stefin/cystatin gene expression correlates with poor clinical outcomes in acute myeloid leukemia patients and discuss the connection of TET deficiency with changes in genome organization. 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 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.
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影响因子：
4.6
作者：
Kundu, Subhadip;Park, Eun Sil;Aplan, Peter D.
通讯作者：
Aplan, Peter D.
影响因子：
3.7
作者：
Bilodeau M;MacRae T;Gaboury L;Laverdure JP;Hardy MP;Mayotte N;Paradis V;Harton S;Perreault C;Sauvageau G
通讯作者：
Sauvageau G
影响因子：
30.5
作者：
Cimmino L;Dawlaty MM;Ndiaye-Lobry D;Yap YS;Bakogianni S;Yu Y;Bhattacharyya S;Shaknovich R;Geng H;Lobry C;Mullenders J;King B;Trimarchi T;Aranda-Orgilles B;Liu C;Shen S;Verma AK;Jaenisch R;Aifantis I
通讯作者：
Aifantis I
影响因子：
24.8
作者：
Lio, Chan-Wang J.;Shukla, Vipul;Rao, Anjana
通讯作者：
Rao, Anjana
DOI：
10.1126/science.aba5545
发表时间：
2021-04-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Klein KN;Zhao PA;Lyu X;Sasaki T;Bartlett DA;Singh AM;Tasan I;Zhang M;Watts LP;Hiraga SI;Natsume T;Zhou X;Baslan T;Leung D;Kanemaki MT;Donaldson AD;Zhao H;Dalton S;Corces VG;Gilbert DM
通讯作者：
Gilbert DM