Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs

Yang, Jiao; Guo, Renpeng; Wang, Hua; Ye, Xiaoying; Zhou, Zhongli; Dan, Jiameng; Wang, Haiying; Gong, Peng; Deng, Wei; Yin, Yu; Mao, Shi Qing; Wang, Lingbo; Ding, Junjun; Li, Jinsong; Keefe, David L.; Dawlaty, Meelad M.; Wang, Jianlong; Xu, Guo Liang; Liu, Lin

doi:10.1016/j.celrep.2016.04.058

Cited by 70 publications

(60 citation statements)

References 64 publications

(111 reference statements)

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“…One of the most established functions for TERRAs is their ability to interfere with telomerase function by acting as a competitive inhibitor for telomere priming 55 , leading to shortened telomeres. In addition, others have shown that decreased 5hmC in murine embryonic stem cells can also lead to telomere shortening 56 , and, as shown here, loss of MECP2 led to decreased 5hmC in hiPSCs (Fig 2). Therefore, we attempted to determine the physiological consequence of TERRA induction in the absence of MECP2.…”

Section: Resultssupporting

confidence: 80%

“…These findings together are highly relevant as DNMT3B is a key de novo methyl transferase to create methylated DNA (5mC), which is the substrate for Tet oxigenases to create 5-hydroxmethylated DNA (5hmC), which is known to be strongly bound by MECP2 63 . Recently, another study showed that deletion of Tet enzymes, which are critical to generate the 5hmC mark, led to shortened telomeres 64,65 . These studies suggest that DNA hydroxymethylation could be important in the regulation of telomere length.…”

Section: Discussionmentioning

confidence: 99%

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Loss of MECP2 leads to activation of p53 and neuronal senescence

Ohashi¹,

Allen²,

Lee³

et al. 2017

Preprint

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27To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic 28 lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient 29 fibroblasts with and without MECP2 expression in an attempt to recapitulate disease 30 phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression 31 changes including induction of a Senescence Associated Secretory Phenotype (SASP) 32 program. Patient derived Neurons made without MECP2 show signs of stress, including 33 induction of p53, and senescence. The induction of p53 appeared to affect dendritic 34 branching in Rett neurons, as p53 inhibition restored dendritic complexity. These 35 disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to 36 an increase in aspects of neuronal aging. 37 38 39 40 41 42 43 44 45 46Rett Syndrome is a disease associated with loss of function mutations in the gene 48 MECP2, which was originally identified as encoding a methylated DNA binding protein 1-49 3 . Patient symptoms include microcephaly, intellectual disability, facial dysmorphia, and 50 seizure activity 4,5 . Studies in murine models recapitulate many of the patient phenotypes 51 and have recently identified a role for MECP2 particularly in inhibitory neurons [6][7][8][9] . These 52 studies demonstrated that loss of MECP2 can lead to defects in transcription 10-12 , 53 dendritic branching 13 , nuclear size 3 , and AKT signaling 14 .54 55 MECP2 has also been described as a transcription factor with specific targets 10,11,13 , and 56 more broadly as either a transcriptional activator 14 or repressor [15][16][17][18] . However, despite 57 decades of research on MECP2, it is still unclear how mutations in this protein lead to 58 patient symptoms 3,14,[19][20][21] . To confirm findings made in other models and further study 59 these in a human system, some have turned to modeling Rett Syndrome in vitro by taking 60 advantage of Disease in a dish approaches. This involves making hiPSCs from patient 61 somatic cells, or using genome engineering to introduce mutations into WT human 62 pluripotent stem cells. In either case, the pluripotent stem cells created are then 63 differentiated toward the neural lineage, and then comparisons can be made between 64 cells that express MECP2 or lack it. 65 66 Some of these studies have even taken advantage of isogenic or congenic cells lines to 67 identify both transcriptional and electrophysiological effects of loss of MECP2 in human 68 4 in vitro models 14,22 . In the current study, we also sought to mitigate the effect of genetic 69 background and variability of differentiation by taking advantage of several congenic lines 70 of hiPSCs that either express the WT allele or the mutant allele leading to cells that 71 express or lack MECP2 23 . This allowed for detailed molecular analyses of hiPSCs, NPCs 72 and neurons with and without MECP2 under the same genetic background. In addition, 73 several lines were made and analyzed in each category to avoid vari...

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Section: Resultssupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Loss of MECP2 leads to activation of p53 and neuronal senescence

Ohashi¹,

Allen²,

Lee³

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…8b). We note that others have recently shown a role for TET enzymes in regulating telomere length, but these effects were only noticeable in TET double- or triple-knockout ESCs 42,43 . Together, these results suggest that fluctuations in ZSCAN4 levels caused by loss of TET1 in naive pluripotent states may have no measurable impact on telomere stability but can be deleterious in primed pluripotency.…”

Section: Resultsmentioning

confidence: 56%

Lineage-specific functions of TET1 in the postimplantation mouse embryo

et al. 2017

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The mammalian TET enzymes catalyze DNA demethylation. While they have been intensely studied as major epigenetic regulators, little is known about their physiological roles and the extent of functional redundancy following embryo implantation. Here we define non-redundant roles for TET1 at an early postimplantation stage of the mouse embryo, when its paralogs Tet2 and Tet3 are not detectably expressed. TET1 regulates numerous genes defining differentiation programs in the epiblast and extraembryonic ectoderm. In epiblast cells, TET1 demethylates gene promoters via hydroxymethylation and maintains telomere stability. Surprisingly, TET1 represses a majority of epiblast target genes independently of methylation changes, in part through regulation of the gene encoding the transcriptional repressor JMJD8. Dysregulated gene expression in the absence of TET1 causes embryonic defects, which are partially penetrant in an inbred strain but fully lethal in non-inbred mice. Collectively, our study highlights an interplay between the catalytic and non-catalytic activities of TET1 that is essential for normal development.

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“…Tet1-deficient mouse embryonic stem cells (mESCs) maintained pluripotency and were largely normal [35], whereas knockout of both Tet1 and Tet2 or three Tets in mESCs showed severe abnormalities in differentiation [36, 37]. It was also reported that knockdown of Tet1 or Tet2 minimally affects pluripotency gene Nanog mRNA expression, but knockdown of both Tet1 and Tet2 reduces Nanog mRNA expression significantly in mESCs [38] and that TET1, TET2, and TET3 are required for the expression of the tumor suppressor gene TCF21 mRNA in cancer cells [39]. Therefore, TET family members have the redundant functions for the expression of certain genes in embryogenesis and tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic upregulation of ARL4C, due to DNA hypomethylation in the 3'-untranslated region, promotes tumorigenesis of lung squamous cell carcinoma

et al. 2016

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ADP-ribosylation factor (ARF)-like 4c (ARL4C) expression, induced by a combination of Wnt/β-catenin and EGF/Ras signaling, has been demonstrated to form epithelial morphogenesis. ARL4C overexpression, due to Wnt/β-catenin and EGF/Ras signaling alterations, was involved in tumorigenesis. It was also reported that ARL4C expression correlates with DNA hypomethylation in the 3’-untranslated region (UTR) of ARL4C gene during lymphogenesis. The current study was conducted to investigate the expression and functions of ARL4C due to DNA hypomethylation in lung and tongue cancers. Immunohistochemical analyses of tissue specimens obtained from lung and tongue squamous cell carcinoma (SCC) patients revealed that ARL4C is not observed in non-tumor regions, but is strongly expressed at high frequencies in tumor lesions. Although inhibition of Wnt/β-catenin or Ras/MAP kinase signaling did not decrease ARL4C expression in NCI-H520 lung SCC cells, ARL4C DNA was clearly hypomethylated in the 3’-UTR. Ten-eleven translocation methylcytosine dioxygenase (TET) enzyme, which mediates DNA demethylation, was highly expressed in NCI-H520 cells. Knockout of TET family proteins (TET1-3) in NCI-H520 cells reduced 5-hydroxymethylcytosine (5hmC) levels and promoted DNA methylation in the 3’-UTR, leading to the decrease in ARL4C expression and ARL4C-mediated cellular migration. In tumor lesions of ARL4C-positive lung SCC, 5hmC was frequently detected and DNA methylation in the 3’-UTR of ARL4C gene was lower than in non-tumor regions, which were consistent with the Cancer Genome Atlas dataset. These results suggest that ARL4C is expressed due to hypomethylation in the 3’-UTR for certain types of cancers and that ARL4C methylation status is involved in cancer cell function.

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Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs

Cited by 70 publications

References 64 publications

Loss of MECP2 leads to activation of p53 and neuronal senescence

Loss of MECP2 leads to activation of p53 and neuronal senescence

Lineage-specific functions of TET1 in the postimplantation mouse embryo

Epigenetic upregulation of ARL4C, due to DNA hypomethylation in the 3'-untranslated region, promotes tumorigenesis of lung squamous cell carcinoma

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