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Computational Molecular Biology 2014, Vol. 4, No. 10, 1-17
http://cmb.biopublisher.ca
11
Previous observations of human stem cells suggested
that histone mono-methylation protected the activation
potentials required for differentiation
,
which seemed to agree with that the data used in this
study was sequenced from T cells in G0/G1 phase and
such cells were poised for activation, partly explaining
why H3K4me1 tended to overlap mono-methylation
of other histone modifications.
3 Discussion
This study highlights the specific associations of
functional genomic features with different H3K4
methylation modifications. It is known from the study
that the differential accumulation of H3K4 at specific
genomic loci represents not only the results of enzyme
catalysis with dynamic changes, but also specific
genomic functions imposed by outer proteins such as
histone methyltransferase. Unfortunately, the causal
relationship between histone modifications and
genomics is still unclear. In this study, we characterize
and statistically compare the genomic and functional
genomic attributes for different combinations of H3K4
methylation with single-localization types as controls.
We find that the distinct H3K4 methylation
combinations have distinct underlying genomic
backgrounds. Histone modification co-localized peaks
tend to mark functionally important regions, such as
protein coding regions and regulatory regions. Such
redundant placement of histone modifications seems
wasteful, but provides a more complex manner to
provide extra information beyond importance.
Functionally important regions such as TFBSs and
exons tend to be more conserved against the bulk
genome, for such regions may be under more selective
constraint
. To protect such
regions, histone modifications can serve as guides for
linking outer signals such as enzyme complexes and
berried DNA signals. Conserved genomic regions are
active regions which need activating epigenetic marks
to cross-talk with outer proteins, especially for the
three methylation states for H3K4 that can form four
distinct types of co-localization. Consistent with prior
studies, the co-localization types except me1me2 are
more conserved than controls, indicating that
co-localizations in H3K4 have underlying conserved
genomic contexts, while the causal relationship
between co-localization and sequence conservation is
elusive. It is possible that distinct methylation
modifications can be enriched in peaks within same
nucleosome or different nucleosomes within close
proximity, from which the recruitment of TrxG and
PcG histone methyltransferase complexes are
considered frequent. Consistent with our expectation,
H3K4me triplet is the most prominent co-localized
type, different from three other types of H3K4me in
that H3K4me triplet is conserved, related to tissue
specificity and is associated with transcription
repressor activity, which prompts us that H3K4me
triplet may be a novel regulator for balancing
activating and repressive transcription, thus H3K4me
triplet can be termed as a “trivalent mark”.
An interesting finding from this study is the specific
association of co-localization with functional
categories which are annotated by GO annotation.
me1me3 twins are associated with transcriptional
regulation and me2me3 twins involve cell activity. As
the me1me2 twins are not robust signals, they are not
evident in the GO study. However, most peaks of
me1me2 are associated with cell part, binding and cell
process. Recent genome-wide histone modification
studies indicate that co-localized H3K4me3/H3K27me3
genomic regions exist for various cell types including
ES, CD4+ T cells and MEF cells
. As
co-localized H3K4me3/H3K27me3 signals specifically
pinpoint functional regions poised for differentiation,
it is straightforward to propose that co-localized
H3K4me signals are largely specific to suppress tissue
differentiation owing to the fact that the histone
methylation profiles in this study were sequenced
from resting T cells and the co-localized H3K4me
regions in the T cell lineage do not express.
Unfortunately, none of significant GO terms
associating with co-localization types is related with
tissue differentiation. Generally, H3K4me co-localizations
are attributed to repression of T cell-specific genes.
But whether the overlapping marks persist when the T
cells are activated is not known.
Distinguishing among H3K4me co-localization types
that have different functions and fully delimiting the
genomic features call for further computational and