Pathway: TET1,2,3 and TDG demethylate DNA
Reactions in pathway: TET1,2,3 and TDG demethylate DNA :
TET1,2,3 and TDG demethylate DNA
About 2-6% of all cytosine residues and 70-80% of cytosine residues in CG dinucleotides in mammalian cells are methylated at the 5 position of the pyrimidine ring. The cytosine residues are methylated by DNA methyltransferases after DNA replication and can be demethylated by passive dilution during subsequent replication or by active modification of the 5-methylcytosine base. Cytosine demethylation is developmentally regulated: one wave of demethylation occurs in primordial germ cells and one wave occurs by active demethylation in the male pronucleus after fertilization.
Some mechanisms of active demethylation remain controversial, however progressive oxidation of the methyl group of 5-methylcytosine followed by base excision by thymine DNA glycosylase (TDG) has been reproducibly demonstrated in vivo (reviewed in Wu and Zhang 2011, Franchini et al 2012, Cadet and Wagner 2013, Kohli and Zhang 2013, Ponnaluri et al. 2013, Rasmussen and Helin 2016). Ten-eleven translocation proteins TET1, TET2, and TET3 are dioxygenases that first oxidize 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) (Tahiliani et al. 2009, Ito et al. 2010), which is found in significant quantities and specific genomic locations in stem cells and neurons (Kinney and Pradhan 2013). TET proteins can further oxidize 5-hmC to 5-formylcytosine (5-fC) and then 5-carboxylcytosine (5-caC) (He et al. 2011, Ito et al. 2011). G:5-fC and G:5-caC base pairs are recognized by TDG, which excises the 5-fC or 5-caC and leaves an abasic site.
TET1 in mouse is expressed in neurons and its expression depends on neuronal activity (Guo et al. 2011, Kaas et al. 2013, Zhang et al. 2013). TET1 is also found in embryonic stem cells (Ficz et al. 2011, Koh et al. 2011, Wu et al. 2011) and in primordial germ cells of mice, where it plays a role in erasure of imprinting (Yamaguchi et al. 2013). TET3 is expressed in oocytes and zygotes of mice and is required for demethylation in the male pronucleus (Gu et al. 2011, Iqbal et al. 2011). TET2 is the most highly expressed TET family protein in hemopoietic stem cells and appears to act as a tumor suppressor. TET2 is also expressed in embryonic stem cells (Koh et al. 2011).
Some mechanisms of active demethylation remain controversial, however progressive oxidation of the methyl group of 5-methylcytosine followed by base excision by thymine DNA glycosylase (TDG) has been reproducibly demonstrated in vivo (reviewed in Wu and Zhang 2011, Franchini et al 2012, Cadet and Wagner 2013, Kohli and Zhang 2013, Ponnaluri et al. 2013, Rasmussen and Helin 2016). Ten-eleven translocation proteins TET1, TET2, and TET3 are dioxygenases that first oxidize 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) (Tahiliani et al. 2009, Ito et al. 2010), which is found in significant quantities and specific genomic locations in stem cells and neurons (Kinney and Pradhan 2013). TET proteins can further oxidize 5-hmC to 5-formylcytosine (5-fC) and then 5-carboxylcytosine (5-caC) (He et al. 2011, Ito et al. 2011). G:5-fC and G:5-caC base pairs are recognized by TDG, which excises the 5-fC or 5-caC and leaves an abasic site.
TET1 in mouse is expressed in neurons and its expression depends on neuronal activity (Guo et al. 2011, Kaas et al. 2013, Zhang et al. 2013). TET1 is also found in embryonic stem cells (Ficz et al. 2011, Koh et al. 2011, Wu et al. 2011) and in primordial germ cells of mice, where it plays a role in erasure of imprinting (Yamaguchi et al. 2013). TET3 is expressed in oocytes and zygotes of mice and is required for demethylation in the male pronucleus (Gu et al. 2011, Iqbal et al. 2011). TET2 is the most highly expressed TET family protein in hemopoietic stem cells and appears to act as a tumor suppressor. TET2 is also expressed in embryonic stem cells (Koh et al. 2011).
Epigenetic processes regulate gene expression by modulating the frequency, rate, or extent of gene expression in a mitotically or meiotically heritable way that does not entail a change in the DNA sequence. Originally the definition applied only to heritability across generations but later also encompassed the heritable changes that occur during cellular differentiation within one organism.
Molecular analysis shows epigenetic changes comprise covalent modifications, such as methylation and acetylation, to DNA and histones. RNA interference has been implicated in the initiation of some epigenetic changes, for example transcriptional silencing of transposons. Proteins which bind to the modified DNA and histones are then responsible for repressing transcription and for maintaining the epigenetic modifications during cell division.
During differentiation, patterns of gene expression are established by polycomb complexes PRC1 and PRC2. PRC2 methylates histones and DNA to produce the initial marks of repression: trimethylated lysine-27 on histone H3 (H3K27me3) and 5-methylcytosine in DNA. PRC2, through its component EZH2 or, in some complexes, EZH1 trimethylates lysine-27 of histone H3. The H3K27me3 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression.
PRC2 and other epigenetic systems modulate gene expression through DNA methyation, the transfer of a methyl group from S-adenosylmethionine to the 5 position of cytosine in DNA by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B.
In the reverse process TET1,2,3 and TDG demethylate DNA through the oxidation of the methyl group of 5-methylcytosine by TET enzymes and the excision of the oxidized product (5-formylcytosine or 5-carboxylcytosine) by TDG.
Ribosomal RNA (rRNA) genes are activated and deactivated according to the metabolic requirements of the cell. Positive epigenetic regulation of rRNA expression occurs through chromatin modifications produced by activators such as ERCC6 (CSB), the B-WICH complex, and histone acetylases such as KAT2B (PCAF). Negative epigenetic regulation of rRNA expression occurs through chromatin modifications produced by repressors such as the eNoSC complex, SIRT1, and the NoRC complex.
WDR5 is a component of six histone methyltransferases and three histone acetyltransferases involved in epigenetic regulation of gene expression (reviewed in Guarnaccia and Tansey 2018).
Molecular analysis shows epigenetic changes comprise covalent modifications, such as methylation and acetylation, to DNA and histones. RNA interference has been implicated in the initiation of some epigenetic changes, for example transcriptional silencing of transposons. Proteins which bind to the modified DNA and histones are then responsible for repressing transcription and for maintaining the epigenetic modifications during cell division.
During differentiation, patterns of gene expression are established by polycomb complexes PRC1 and PRC2. PRC2 methylates histones and DNA to produce the initial marks of repression: trimethylated lysine-27 on histone H3 (H3K27me3) and 5-methylcytosine in DNA. PRC2, through its component EZH2 or, in some complexes, EZH1 trimethylates lysine-27 of histone H3. The H3K27me3 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression.
PRC2 and other epigenetic systems modulate gene expression through DNA methyation, the transfer of a methyl group from S-adenosylmethionine to the 5 position of cytosine in DNA by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B.
In the reverse process TET1,2,3 and TDG demethylate DNA through the oxidation of the methyl group of 5-methylcytosine by TET enzymes and the excision of the oxidized product (5-formylcytosine or 5-carboxylcytosine) by TDG.
Ribosomal RNA (rRNA) genes are activated and deactivated according to the metabolic requirements of the cell. Positive epigenetic regulation of rRNA expression occurs through chromatin modifications produced by activators such as ERCC6 (CSB), the B-WICH complex, and histone acetylases such as KAT2B (PCAF). Negative epigenetic regulation of rRNA expression occurs through chromatin modifications produced by repressors such as the eNoSC complex, SIRT1, and the NoRC complex.
WDR5 is a component of six histone methyltransferases and three histone acetyltransferases involved in epigenetic regulation of gene expression (reviewed in Guarnaccia and Tansey 2018).
Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition.