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of the hypothalamus, where it acts as an alternative promoter of the
Cdh15
transcript, only active on the unmethylated paternal allele. A hypothalamus-
specific transcription factor may be involved in this tissue-specific mainte-
nance of parental asymmetry. Systematic studies of different tissues and at
different ages must be conducted to truly determine how permanently
maintained the ICRs are. In this regard, although a genome-wide survey
of maternal-specific DNA methylation uncovered around 30 new maternal
ICR candidates in the midgestation mouse embryo (
Proudhon et al., 2012
),
only nine ICR candidates were identified in the adult cortex specifically
(
Xie et al., 2012
). As a whole, embryonic differentiation at implantation
and tissue differentiation throughout life gradually restrain the number of
ICRs, reducing the occurrence of parental epigenetic asymmetry step by
step to just a few dozen loci.
5.2. Emergence of somatic DMRs
Most germline DMRs disappear in the wake of the embryonic
de novo
DNA
methylation associated with peri-implantation development. However, as a
counterbalance, new loci acquire parent-specific DNA methylation at this
stage, outside the germline context. These are called the secondary, som-
DMRs (
Fig. 9.2
). Distinction of the parental genomes occurs within the
same nuclear environment, via germline, primary ICRs located in the vicin-
ity and acting
in cis
. somDMRs are associated with the monoallelic, parent-
specific expression of surrounding genes and, like ICRs, harbor opposite
states of histone modifications (see
Section 5.3
). Postimplantation emer-
gence of somDMRs is a very common theme, found at many imprinted loci
including
Dlk1
-
Gtl2
,
Gnas
,
Gpr1
-
Zdbf2
,
H19
-
Ig f2
,
Airn
-
Ig f2r
, and
Kcnq1
(reviewed in
John & Lefebvre, 2011
). Acquisition of methylation at som-
DMRs is associated with transcription
in cis
, of either protein-coding genes
or noncoding RNAs, whose promoter is regulated by an ICR. The act of
transcription rather than the transcript product is usually required for
the acquisition of somDMRs on the same allele (
Latos et al., 2012
). The pre-
cise molecular mechanisms for transcription-dependent somDMR emer-
gence merit further attention.
5.3. Parent-specific histone modifications at imprinted loci
ICRs and somDMRs typically harbor parent-specific histone modifications,
with the unmethylated allele marked by permissive H3K4me2/3 and
H3K9ac modifications, and the methylated allele marked by a combination
