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This thread will go into the bodies mechanism for active demethylation
Writing this thread because you will need to understand it for my next thread.
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Active DNA demethylation refers to the enzymatic, replication-independent removal of methyl groups from DNA (specifically 5-methylcytosine, or 5mC) in mammalian cells, including the human body. This process is crucial for dynamic gene regulation during embryonic development, cell differentiation, reprogramming, and responses in post-mitotic cells like neurons.
It contrasts with passive demethylation, which occurs when maintenance methylation (by DNMT1) is inhibited during DNA replication, leading to gradual dilution of 5mC over cell divisions. Active demethylation, however, directly reverses methylation without requiring replication.
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The dominant pathway for active DNA demethylation in mammals is mediated by TET (Ten-Eleven Translocation) enzymes (TET1, TET2, TET3). These are Fe(II)- and α-ketoglutarate-dependent dioxygenases that iteratively oxidize 5mC. The oxidized intermediates are then processed by thymine-DNA glycosylase (TDG) and the base excision repair (BER) machinery to restore unmodified cytosine.
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The sequence in which it works
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Oxidation by TET enzymes:
TET proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).
Further oxidation produces 5-formylcytosine (5fC).
Final oxidation yields 5-carboxylcytosine (5caC).
These steps occur in an Fe(II)/α-ketoglutarate-dependent manner and can happen at specific genomic loci (e.g., enhancers, gene bodies, or promoters) recruited by transcription factors or RNA polymerase II.
Excision by TDG:
TDG specifically recognizes and excises 5fC or 5caC (but not 5hmC efficiently), creating an abasic (AP) site
Base excision repair (BER):
The AP site is processed by APE1 (endonuclease), DNA polymerase β (fills in the gap with unmodified cytosine), and ligase to complete repair.
The net result: 5mC to C (unmethylated cytosine.
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Going to explain how we can utilize it in my next thread.
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determinism
Writing this thread because you will need to understand it for my next thread.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Active DNA demethylation refers to the enzymatic, replication-independent removal of methyl groups from DNA (specifically 5-methylcytosine, or 5mC) in mammalian cells, including the human body. This process is crucial for dynamic gene regulation during embryonic development, cell differentiation, reprogramming, and responses in post-mitotic cells like neurons.
It contrasts with passive demethylation, which occurs when maintenance methylation (by DNMT1) is inhibited during DNA replication, leading to gradual dilution of 5mC over cell divisions. Active demethylation, however, directly reverses methylation without requiring replication.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
The dominant pathway for active DNA demethylation in mammals is mediated by TET (Ten-Eleven Translocation) enzymes (TET1, TET2, TET3). These are Fe(II)- and α-ketoglutarate-dependent dioxygenases that iteratively oxidize 5mC. The oxidized intermediates are then processed by thymine-DNA glycosylase (TDG) and the base excision repair (BER) machinery to restore unmodified cytosine.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
The sequence in which it works
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Oxidation by TET enzymes:
TET proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).
Further oxidation produces 5-formylcytosine (5fC).
Final oxidation yields 5-carboxylcytosine (5caC).
These steps occur in an Fe(II)/α-ketoglutarate-dependent manner and can happen at specific genomic loci (e.g., enhancers, gene bodies, or promoters) recruited by transcription factors or RNA polymerase II.
Excision by TDG:
TDG specifically recognizes and excises 5fC or 5caC (but not 5hmC efficiently), creating an abasic (AP) site
Base excision repair (BER):
The AP site is processed by APE1 (endonuclease), DNA polymerase β (fills in the gap with unmodified cytosine), and ligase to complete repair.
The net result: 5mC to C (unmethylated cytosine.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Going to explain how we can utilize it in my next thread.



