Epigenetic gene regulation by TET3 and 5-hydroxymethylcytosine during retinal maturation
Beschreibung
vor 9 Jahren
The 2-oxoglutarate and Fe (II)-dependent ten-eleven translocation
(TET) enzymes can oxidize 5-methylcytosine (5mC) to
5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and
5-carboxycytosine (5caC). Thus, it was hypothesized that this could
be a pathway for active DNA demethylation. However, several studies
have shown that 5hmC levels accumulate especially in neurons
suggesting a role as an epigenetic mark. Nevertheless, the
mechanism controlling TET activity and the role of 5hmC are poorly
understood. In particular, it is not known how the neuronal TET3
isoform lacking a DNA binding domain is targeted to the DNA. In
this study, the role of 5hmC during retinal maturation by
genome-wide mapping of 5hmC in immature (postnatal week 2) and
mature mouse retina (postnatal week 3) was studied and correlated
with expression data. Furthermore, interaction partners of
neu-ronal TET3, the main isoform in retinal neurons, were
identified. 5hmC accumulates during retinal maturation especially
in retinal and neuronal genes. Furthermore, the accumulation of
5hmC is associated with increased transcription. Among the
identified proteins the transcriptional repressor REST was
identified as a highly enriched TET3-specific interactor.
Interestingly, REST was able to enhance TET3 hydroxylase activity.
Furthermore, increased 5hmC levels were detected in REST target
genes during retinal maturation and overexpression of TET3
activated transcription of REST-target genes. Moreover, NSD3 and
two other histone methyltransferases were found to interact with
TET3 that are able to mediate H3K36 trimethylation. Finally, it was
shown that TET3 is able to enhance NSD3-mediated H3K36
trimethylation to pro-mote transcriptional activation. In
conclusion, the data suggests that 5hmC is a stable epigenetic base
in retinal neurons that is involved in transcriptional activation.
Furthermore, it was shown that 5hmC is generated by TET3 that is
recruited to the DNA by transcriptional regulators such as REST in
a context-specific manner.
(TET) enzymes can oxidize 5-methylcytosine (5mC) to
5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and
5-carboxycytosine (5caC). Thus, it was hypothesized that this could
be a pathway for active DNA demethylation. However, several studies
have shown that 5hmC levels accumulate especially in neurons
suggesting a role as an epigenetic mark. Nevertheless, the
mechanism controlling TET activity and the role of 5hmC are poorly
understood. In particular, it is not known how the neuronal TET3
isoform lacking a DNA binding domain is targeted to the DNA. In
this study, the role of 5hmC during retinal maturation by
genome-wide mapping of 5hmC in immature (postnatal week 2) and
mature mouse retina (postnatal week 3) was studied and correlated
with expression data. Furthermore, interaction partners of
neu-ronal TET3, the main isoform in retinal neurons, were
identified. 5hmC accumulates during retinal maturation especially
in retinal and neuronal genes. Furthermore, the accumulation of
5hmC is associated with increased transcription. Among the
identified proteins the transcriptional repressor REST was
identified as a highly enriched TET3-specific interactor.
Interestingly, REST was able to enhance TET3 hydroxylase activity.
Furthermore, increased 5hmC levels were detected in REST target
genes during retinal maturation and overexpression of TET3
activated transcription of REST-target genes. Moreover, NSD3 and
two other histone methyltransferases were found to interact with
TET3 that are able to mediate H3K36 trimethylation. Finally, it was
shown that TET3 is able to enhance NSD3-mediated H3K36
trimethylation to pro-mote transcriptional activation. In
conclusion, the data suggests that 5hmC is a stable epigenetic base
in retinal neurons that is involved in transcriptional activation.
Furthermore, it was shown that 5hmC is generated by TET3 that is
recruited to the DNA by transcriptional regulators such as REST in
a context-specific manner.
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