Loss of Tet Enzymes Compromises Proper Differentiation of Embryonic Stem Cells

Dawlaty, Meelad M.; Breiling, Achim; Le, Thuc T.; Barrasa, M. Inmaculada; Raddatz, Günter; Gao, Qing; Powell, Benjamin E.; Cheng, Albert W.; Faull, Kym F.; Lyko, Frank; Jaenisch, Rudolf

doi:10.1016/j.devcel.2014.03.003

Cited by 297 publications

(280 citation statements)

References 33 publications

(56 reference statements)

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“…S6B). Consistent with a previous report (45), neuroectoderm and cardiac mesoderm markers were all decreased during differentiation of Tet1/2/3 TKO mESCs in serum-containing cultures compared with the WT controls ( Fig. S6 C and D).…”

Section: Phenotype Of Tet3-deficient Mescs Is Exacerbated By Concurrentsupporting

confidence: 80%

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

Yue

Pastor

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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TET-family dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and oxidized methylcytosines in DNA. Here, we show that mouse embryonic stem cells (mESCs), either lacking Tet3 alone or with triple deficiency of Tet1/2/3, displayed impaired adoption of neural cell fate and concomitantly skewed toward cardiac mesodermal fate. Conversely, ectopic expression of Tet3 enhanced neural differentiation and limited cardiac mesoderm specification. Genome-wide analyses showed that Tet3 mediates cell-fate decisions by inhibiting Wnt signaling, partly through promoter demethylation and transcriptional activation of the Wnt inhibitor secreted frizzled-related protein 4 (Sfrp4). Tet1/2/3-deficient embryos (embryonic day 8.0–8.5) showed hyperactivated Wnt signaling, as well as aberrant differentiation of bipotent neuromesodermal progenitors (NMPs) into mesoderm at the expense of neuroectoderm. Our data demonstrate a key role for TET proteins in modulating Wnt signaling and establishing the proper balance between neural and mesodermal cell fate determination in mouse embryos and ESCs.

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Section: Phenotype Of Tet3-deficient Mescs Is Exacerbated By Concurrentsupporting

confidence: 80%

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

Yue

Pastor

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…5hmC is enriched in wild type (WT) murine embryonic stem (ES) cells, such that TET1/2/3 KO ES cells are dramatically depleted of 5hmC and exhibit poorly differentiated embryonic bodies and teratomas [13]. Promoter DNA in these embryos is hypermethylated, and genes involved in embryonic development and differentiation are deregulated.…”

Section: Introductionmentioning

confidence: 99%

Roles of IDH1/2 and TET2 mutations in myeloid disorders

2016

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Although mutated IDH1/2 are clearly established as oncogenes in myeloid cells, the mechanisms underlying their tumorigenic effects are not clear. Much evidence suggests that mutant IDH enzymes exert their effects via inhibition of TET2, but important clinical differences between IDH1-mutant and TET2-mutant hematopoietic disorders suggest that the oncogenic mechanisms of these mutated enzymes may differ. In particular, divergent effects of mutant IDH1/2 and TET2 on DNA damage repair mechanisms have been identified. In this review, we examine mutant IDH1/2 and TET2 in the context of responses to DNA damage and their potential involvement in genomic instability. We also discuss the clinical relevance of these findings and their potential application in novel therapeutic strategies. Mutation of TET family enzymesThe TET family of dioxygenases is highly conserved and contains three members: TET1, -2 and -3. Somatic mutations of TET2 occur in various myeloid disorders, including chronic myelomonocytic leukemia (CMML) (~50 %), myeloid proliferative neoplasm (MPN) (~13 %), MDS (~25 %) and AML (~23 %) [1,2]. TET2 is also mutated in B and T cell lymphoid malignancies, including angioimmunoblastic T cell lymphoma (AITL) [3]. More recently, TET2 mutations have been detected in elderly individuals with clonal hematopoiesis of indeterminate potential, i.e.: individuals with clonal hematopoiesis without identified hematological disease. This indicates that TET2 mutations alone cannot drive leukemogenesis and that additional events probably contribute [4,5]. Interestingly, TET1 and TET3 mutations are rare in human hematological diseases [6]. This predominance of TET2 alterations is not Abstract Mutations of the epigenetic enzymes isocitrate dehydrogenase (IDH) 1 and 2, and the methylcytosine dioxygenase 'ten-eleven translocation 2' (TET2), are common in human myeloid malignancies and drivers of these disorders but the underlying mechanisms remain obscure. This review examines mutant IDH1/2 and TET2 enzymes in the context of responses to DNA damage and their potential involvement in age-related genomic instability. The clinical relevance of these findings and their potential application in novel therapeutic strategies is also discussed.

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“…This relatively mild embryonic phenotype could reflect the potential involvement of Tet3, which is up-regulated compared with control (CTL) in embryonic stem (ES) cells, embryonic day 13.5 (E13.5) embryos, and adult brain and lung of Tet1/2 DKO mice (20). Tet3 is likely to be an important player, because triple Tet1/2/3-deficient ES cells show significant defects in differentiation (21) and triple TET-deficient mouse embryonic fibroblasts cannot be reprogrammed to induced pluripotent stem cells (22). Thus, a complete characterization of the roles of TET proteins and oxi-mC modifications in early embryogenesis will require significant interference with TET function, through analysis of embryos deficient for Tet1/Tet3, Tet2/Tet3, or all of the three TET proteins.…”

mentioning

confidence: 99%

Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

Kang

Lienhard

Pastor

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

101

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Dioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.DNA methylation | cholesterol biosynthesis | TET methylcytosine oxidases | 5-hydroxymethylcytosine | 5hmC

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Loss of Tet Enzymes Compromises Proper Differentiation of Embryonic Stem Cells

Cited by 297 publications

References 33 publications

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

Roles of IDH1/2 and TET2 mutations in myeloid disorders

Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis

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