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Volume 3, Issue 4
J Clin Epigenet
ISSN: 2472-1158
Epigenetics 2017
November 06-08, 2017
EPIGENETICS & CHROMATIN
November 06-08, 2017 | Frankfurt, Germany
2
nd
International Congress on
J Clin Epigenet 2017, 3:4
DOI: 10.21767/2472-1158-C1-003
Methyl-CpG binding proteins: Guardians of the epigenome
M Cristina Cardoso
Technische Universität Darmstadt, Germany
A
ll members of the Methyl-CpG-binding domain (MBD) protein family, except for MBD3, have been described to bind
with high affinity to single methyl-CpG di-nucleotides, thereby silencing gene expression and dampening transcriptional
noise of highly methylated, repetitive elements. In contrast, Ten-Eleven-Translocation (TET) proteins were shown to catalyze
the conversion of 5 mC to 5 hmC, 5 fC and 5 caC in an iterative, Fe(II)-and oxoglutarate-dependent oxidation reaction,
which is followed by the erasure of the repressing epigenetic mark. In this context, we aimed to elucidate the interplay of
the MBD protein family and the recently described TET-mediated, active demethylation process. To this end, we quantified
and compared global levels of 5 mC and its derivatives, transcriptional level, genomic stability and chromatin structure in
human and murine cells as physiological consequences of 5 mC elimination. Moreover, we extended these analyses to the loss
of function of the X-linked MECP2 gene, which causes Rett syndrome, a debilitating neurological disorder. We show that
Mecp2 and Mbd2 protect 5 mC from Tet1-mediated oxidation in a concentration dependent manner
in vivo
and
in vitro
. The
protection mechanism is not based on competition for 5 mC per se but rather on sequence unspecific coverage of DNA and
correlates with the respective MBD protein dwell time on DNA. As a biological consequence, we measured increased 5 hmC
level in neurons of a mouse model for Rett syndrome with concomitant reactivation of epigenetically silenced peri-centric
DNA repeats.