A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity

Song, Xiaosheng; Yang, Liuliu; Wang, Mingzhu; Gu, Yue; Ye, Buqing; Fan, Zusen; Xu, Rui-Ming; Yang, Na

doi:10.1073/pnas.1904672116

Cited by 20 publications

(25 citation statements)

References 30 publications

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“…Zc3h10 binds to Dot1l via the 501-1000aa fragment, which is largely composed of coiled coil domains, evolutionarily conserved and widely-known for protein-protein interactions (Mier et al, 2017). This same coiled coil domain has been reported to interact with some of mixed lineage leukemia (MLL) oncogenic fusion proteins, such as AF10, to induce H3K79 methylation and constitutively activate a leukemic transcription program (Song et al, 2019). Here, we show that Dot1l is required for Zc3h10's function for thermogenic gene program.…”

Section: Discussionmentioning

confidence: 99%

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Nguyen

Dinh

et al. 2020

eLife

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Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1l, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the Ucp1 promoter and other BAT genes. Through a direct interaction, Dot1l is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1l is induced during brown fat cell differentiation and by cold exposure and that Dot1l and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1l ablation in mice using Ucp1-Cre prevents activation of Ucp1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1l plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.

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Section: Discussionmentioning

confidence: 99%

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Nguyen

Dinh

et al. 2020

eLife

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“…A recent study also showed that a cofactor of DOT1L AF10, which is highly expressed in mouse LSK cells, can facilitate the methyltransferase activity of DOT1L to obtain higher order H3K79 methylation [14]. Recently, AF10 has been verified to bind to CC0 (amino acids 483 to 502) and a longer CC1 helix (amino acids 510 to 549) of DOT1L in MLL-AF10 leukemia [59]; both domains are near to the K-rich region that LAMP5-AS1 interacted with, suggesting that LAMP5-AS1 and AF10 might cooperate to enhance the methyltransferase activity of DOT1L in MLL leukemia. Taken together, these results explain the specific oncogenicity of the ubiquitously expressed DOT1L from another perspective.…”

Section: Discussionmentioning

confidence: 98%

The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia

et al. 2020

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Background: Mixed-lineage leukemia (MLL) gene rearrangements trigger aberrant epigenetic modification and gene expression in hematopoietic stem and progenitor cells, which generates one of the most aggressive subtypes of leukemia with an apex self-renewal. It remains a challenge to directly inhibit rearranged MLL itself because of its multiple fusion partners and the poorly annotated downstream genes of MLL fusion proteins; therefore, novel therapeutic targets are urgently needed. Methods: qRT-PCR, receiver operating characteristic (ROC), and leukemia-free survival analysis were used to validate LAMP5-AS1 (LAMP5 antisense 1) expression and evaluate its clinical value. We performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5-AS1 in MLL leukemia progression and leukemia cell stemness. RNA electrophoretic mobility shift assays (EMSA), histone methyltransferase assay, RNA pull-down assay, and RNA fluorescence in situ hybridization (FISH) were used to validate the relationship between LAMP5-AS1 and the methyltransferase activity of DOT1L. The downstream ectopic target genes of LAMP5-AS1/DOT1L were validated by the chromatin immunoprecipitation (ChIP) and western blot. Results: We discovered that a long noncoding RNA (lncRNA) LAMP5-AS1 can promote higher degrees of H3K79 methylation, followed by upregulated expression of the self-renewal genes in the HOXA cluster, which are responsible for leukemia stemness in context of MLL rearrangements. We found that LAMP5-AS1 is specifically overexpressed in MLL leukemia patients (n = 58) than that in the MLL-wt leukemia (n = 163) (p < 0.001), and the patients with a higher expression level of LAMP5-AS1 exhibited a reduced 5-year leukemia-free survival (p < 0.01). LAMP5-AS1 suppression significantly reduced colony formation and increased differentiation of primary MLL leukemia CD34+ cells. Mechanistically, LAMP5-AS1 facilitated the methyltransferase activity of DOT1L by directly binding its Lys-rich region of catalytic domain, thus promoting the global patterns of H3K79 dimethylation and trimethylation in cells. These observations supported that LAMP5-AS1 upregulated H3K79me2/me3 and the

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“…This same coiled coil domain has been reported to interact with some of mixed lineage leukemia (MLL) oncogenic fusion proteins, such as AF10, to induce H3K79 methylation and constitutively activate a leukemic transcription program (Song et al, 2019). Here, we show that Dot1L is required for Zc3h10's function for thermogenic gene program.…”

Section: Discussionmentioning

confidence: 60%

Dot1L interacts with Zc3h10 to activate UCP1 and other thermogenic genes

Yi¹,

Nguyen²,

Dinh³

et al. 2020

Preprint

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13Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical 14 energy into heat, thereby increasing energy expenditure. Here, we identify Dot1L, the only 15 known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally 16 activates the UCP1 promoter and other BAT genes. Through a direct interaction, Dot1L is 17 recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator 18 by methylating H3K79. We also show that Dot1L is induced during brown fat cell differentiation 19 and by cold exposure and that Dot1L and its H3K79 methyltransferase activity is required for 20 thermogenic gene program. Furthermore, we demonstrate that Dot1L ablation in mice using 21 UCP1-Cre prevents activation of UCP1 and other target genes to reduce thermogenic capacity 22 and energy expenditure, promoting adiposity. Hence, Dot1L plays a critical role in the 23 thermogenic program and may present as a future target for obesity therapeutics. 24 25 42 UCP1 gene. A multitude of transcriptional regulators have been implicated in the transcription of 43 UCP1, including transcription factors, Zfp516, IRF4 and EBF2, and transcriptional coregulators,

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A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity

Cited by 20 publications

References 30 publications

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

Dot1l interacts with Zc3h10 to activate Ucp1 and other thermogenic genes

The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia

Dot1L interacts with Zc3h10 to activate UCP1 and other thermogenic genes

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