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Elife
2017 ; 6
(?): ? Nephropedia Template TP
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Oncometabolite D-2-Hydroxyglutarate enhances gene silencing through inhibition of
specific H3K36 histone demethylases
#MMPMID28346139
Janke R
; Iavarone AT
; Rine J
Elife
2017[Mar]; 6
(?): ? PMID28346139
show ga
Certain mutations affecting central metabolism cause accumulation of the
oncometabolite D-2-hydroxyglutarate which promotes progression of certain tumors.
High levels of D-2-hydroxyglutarate inhibit the TET family of DNA demethylases
and Jumonji family of histone demethylases and cause epigenetic changes that lead
to altered gene expression. The link between inhibition of DNA demethylation and
changes in expression is strong in some cancers, but not in others. To determine
whether D-2-hydroxyglutarate can affect gene expression through inhibiting
histone demethylases, orthologous mutations to those known to cause accumulation
of D-2-hydroxyglutarate in tumors were generated in Saccharomyces cerevisiae,
which has histone demethylases but not DNA methylases or demethylases.
Accumulation of D-2-hydroxyglutarate caused inhibition of several histone
demethylases. Inhibition of two of the demethylases that act specifically on
histone H3K36me2,3 led to enhanced gene silencing. These observations pinpointed
a new mechanism by which this oncometabolite can alter gene expression, perhaps
repressing critical inhibitors of proliferation.
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