The Intrinsic and Extrinsic Effects of Tet Proteins During Gastrulation

2021 ◽  
Author(s):  
Saifeng Cheng ◽  
Markus Mittnenzweig ◽  
Yoav Mayshar ◽  
Aviezer Lifshitz ◽  
Marko Dunjic ◽  
...  
Keyword(s):  
Tet Proteins ◽  
Extrinsic Effects

scholarly journals Neuroblastoma and the epigenome

2021 ◽  
Author(s):  
Irfete S. Fetahu ◽  
Sabine Taschner-Mandl
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Disease Diagnosis ◽  
Dna Methyltransferases ◽  
Epigenetic Alterations ◽  
Aberrant Expression ◽  
Tet Proteins ◽  
Relative Paucity ◽  
Underlying Causes ◽  
Aberrant Dna Methylation

AbstractNeuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system and one of the most common solid tumors in infancy. Amplification of MYCN, copy number alterations, numerical and segmental chromosomal aberrations, mutations, and rearrangements on a handful of genes, such as ALK, ATRX, TP53, RAS/MAPK pathway genes, and TERT, are attributed as underlying causes that give rise to NB. However, the heterogeneous nature of the disease—along with the relative paucity of recurrent somatic mutations—reinforces the need to understand the interplay of genetic factors and epigenetic alterations in the context of NB. Epigenetic mechanisms tightly control gene expression, embryogenesis, imprinting, chromosomal stability, and tumorigenesis, thereby playing a pivotal role in physio- and pathological settings. The main epigenetic alterations include aberrant DNA methylation, disrupted patterns of posttranslational histone modifications, alterations in chromatin composition and/or architecture, and aberrant expression of non-coding RNAs. DNA methylation and demethylation are mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, respectively, while histone modifications are coordinated by histone acetyltransferases and deacetylases (HATs, HDACs), and histone methyltransferases and demethylases (HMTs, HDMs). This article focuses predominately on the crosstalk between the epigenome and NB, and the implications it has on disease diagnosis and treatment.

scholarly journals The chromosomal protein SMCHD1 regulates DNA methylation and the 2c-like state of embryonic stem cells by antagonizing TET proteins

2021 ◽  
Vol 7 (4) ◽  
pp. eabb9149
Author(s):  
Zhijun Huang ◽  
Jiyoung Yu ◽  
Wei Cui ◽  
Benjamin K. Johnson ◽  
Kyunggon Kim ◽  
...  
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Homeobox Gene ◽  
Dna Demethylation ◽  
Chromosomal Protein ◽  
Dna Hypomethylation ◽  
Tet Proteins ◽  
Target Sites ◽  
Structural Maintenance Of Chromosomes ◽  
Hinge Domain

5-Methylcytosine (5mC) oxidases, the ten-eleven translocation (TET) proteins, initiate DNA demethylation, but it is unclear how 5mC oxidation is regulated. We show that the protein SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) is found in complexes with TET proteins and negatively regulates TET activities. Removal of SMCHD1 from mouse embryonic stem (ES) cells induces DNA hypomethylation, preferentially at SMCHD1 target sites and accumulation of 5-hydroxymethylcytosine (5hmC), along with promoter demethylation and activation of the Dux double-homeobox gene. In the absence of SMCHD1, ES cells acquire a two-cell (2c) embryo–like state characterized by activation of an early embryonic transcriptome that is substantially imposed by Dux. Using Smchd1/Tet1/Tet2/Tet3 quadruple-knockout cells, we show that DNA demethylation, activation of Dux, and other genes upon SMCHD1 loss depend on TET proteins. These data identify SMCHD1 as an antagonist of the 2c-like state of ES cells and of TET-mediated DNA demethylation.

Extrinsic effects in the dynamics and selection of cellular arrays

10.2514/3.508 ◽  
1994 ◽  
Vol 8 (1) ◽  
pp. 113-118 ◽  
Author(s):  
B. Billia ◽  
H. Jamgotchian ◽  
H. Nguyen Thi ◽  
P. Cerisier ◽  
R. Trivedi
Keyword(s):  
Extrinsic Effects ◽  
Selection Of ◽  
Cellular Arrays

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

2015 ◽  
Vol 112 (31) ◽  
pp. E4236-E4245 ◽  
Author(s):  
Jinsuk Kang ◽  
Matthias Lienhard ◽  
William A. Pastor ◽  
Ashu Chawla ◽  
Mark Novotny ◽  
...  
Keyword(s):  
Single Cells ◽  
Cholesterol Biosynthesis ◽  
Early Embryogenesis ◽  
Dna Demethylation ◽  
Cell Stage ◽  
Tet Proteins ◽  
Genes Encoding ◽  
Variable Gene ◽  
Intracellular Pathways ◽  
Tet Enzymes

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.

scholarly journals TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells

2017 ◽  
Vol 50 (1) ◽  
pp. 83-95 ◽  
Author(s):  
Nipun Verma ◽  
Heng Pan ◽  
Louis C. Doré ◽  
Abhijit Shukla ◽  
Qing V. Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
De Novo ◽  
Embryonic Stem ◽  
Tet Proteins ◽  
De Novo Methylation
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