Biology Reference
In-Depth Information
more modest magnitude, have been obtained by our group in initial pheno-
typic and hormonal analyses of rat models of central pharmacological mani-
pulation of methylation or deacetylation during the pubertal transition
(Leon, Castellano, & Tena-Sempere, unpublished). The mechanismwhere-
by methylation-induced suppression of PcG repressors induces the onset of
puberty likely involves the activation of
Kiss1
expression, and prevention of
this phenomenon resulted in delayed puberty (
Lomniczi et al., 2013
). Alto-
gether, the above findings suggest that the tempo of puberty is finely con-
trolled by inhibitory mechanisms that are lifted at the time of pubertal
maturation by methylation changes, thus allowing the increase in hypotha-
lamic
Kiss1
expression (and likely activity) that characterizes the onset of
puberty (
Lomniczi et al., 2013
). In line with this phenomenon, recent obser-
vations strongly suggest that the differential methylation of the
Kiss1
gene
might contribute to the dimorphism in the expression levels of
Kiss1
in
the RP3V between male and female rodents (
Semaan, Dhamija, Kim,
Ku, & Kauffman, 2012
), which arises in part during the pubertal transition.
In addition, estrogen-induced changes in histone acetylation at the
Kiss1
promoter in this rostral area may play a role in the positive feedback respon-
sible for the generation of the preovulatory surge (
Tomikawa et al., 2012
);
a finding that stresses the importance of epigenetic regulatory mechanisms
in the control of the Kiss1 system.
In addition to epigenetic changes, miRNA regulatory pathways might
also be involved in the control of pubertal maturation; yet, the available evi-
dence remains (mostly) circumstantial and needs to be thoroughly validated
from a functional standpoint. In this context, in 2009, four independent
genome-wide association studies identified an association of the age at men-
arche with variability at 6q21, in or near the
Lin28B
gene (
He et al., 2009;
Ong et al., 2009; Perry et al., 2009; Sulem et al., 2009
). The robustness of
this finding was later confirmed by an extensive meta-analysis (
Elks et al.,
2010
), and the fact that Lin28B has also been linked to breast development
and adult height. Furthermore, over-expression of the related Lin28A was
shown to delay puberty in mice (
Zhu et al., 2010
), among other phenotypic
features. While the mechanisms for such a pubertal role of Lin28 proteins is
yet to be exposed, it was interesting to note that Lin28s are RNA-binding
proteins whose major known function is to block the processing of miRNAs
of the
let-7
family, via inhibition of the maturation of
let-7
precursors (
Heo
et al., 2008; Viswanathan, Daley, & Gregory, 2008
). This was the first (indi-
rect) suggestion of the potential involvement of miRNAs, of the
let-7
family
and/or other related groups, in the regulation of puberty.
