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antibodies against histone post-translational modifications
[142]
or histone variants
[143]
rather than transcription
factors. Clustering the data from ChIP-CHIP experiments
mapping 19 histone modifications and eight chromatin-
associated proteins revealed five groups of marks associ-
ated with X chromosome silencing, gene activation and
gene repression. Moreover at the chromosome scale, the
pattern of histone modifications mirrored those of gene
expression, with repressive marks concentrated in the
regions of elevated meiotic recombination in the chromo-
some arms
[142]
. Similarly, genome-wide maps of chro-
mosome binding by the dosage compensation complex
responsible for downregulation of gene expression from
both X chromosomes in hermaphrodites have been con-
structed, revealing extensive binding at transcription start
sites
[144]
and sequence-independent propagation of the
complex from X-linked recruitment sites
[145]
.
Perhaps one of the most interesting insights obtained
from these genome-wide maps of chromatin organization is
evidence for the epigenetic transmission of information from
the germline to the zygote
[146]
. Mapping the binding sites
of the H3K36 methyltransferaseMES-4 in embryos revealed
a striking correlation betweenMES-4 binding and genes that
were previously expressed in the maternal germline
[146]
.
Together with the semi-stable transmission of RNAi-induced
chromatin states
[147]
and phenotypes
[148]
, this provides
genome-wide evidence for the transmission of chromatin
states across generations. As for transcription factors,
a major issue with mapping chromatin states in C. elegans is
the diversity of cell types present in a typical sample. To date,
cell-type specific maps of chromatin modifications have not
been produced. Also, chromatin confirmation capture-based
approaches to map the three-dimensional organization of
chromosomes in the nucleus (see Chapter 7) have not yet
been applied to C. elegans.
inter-individual phenotypic variation in C. elegans,
focusing both on the causes of phenotypic variation in
wild-type individuals
[149
152]
and on the causes of
inter-individual variation in the outcome of mutations
[133,134,149]
.
One of the most striking phenotypes with inter-individual
variation in both humans andworms is lifespan. In laboratory
conditions, C. elegans has a lifespan of about 2 weeks, but
there is substantial variation in lifespan between isogenic
individuals even on the same agar plate
[152,153]
. Several
studies have now identified gene expression variation that
can predict with reasonable accuracy the remaining lifespan
of individuals part way through their life
[150
e
152]
. The
first of these studies focused on variation in lifespan after the
application of a lifespan-extending heat stress
[151]
.
Animals experiencing a mild environmental stress such as
a heat shock induce the expression of molecular chaperones,
and display an extended lifespan. Using an hsp-16.2
e
GFP
reporter construct and a 'worm sorter' to quantify expression
in individual worms revealed substantial variation in the
induction of chaperones after a heat stress. Moreover, sepa-
rating individuals according to their levels of chaperone
induction revealed that those with higher chaperone
expression tended to live longer
[151]
. Variation in hsp-16.2
induction correlates with inter-individual variation in the
duration of stress signaling, and so likely reflects pre-existing
molecular heterogeneity in a population
[149]
. This hetero-
geneitymight reflect a fitness trade-off between reproductive
development and stress resistance: although individuals with
higher chaperone expression live longer and are more stress
resistant, they develop more slowly and so will be out-
competed in benign conditions
[149]
.
More recently, reporters have also been described that
can predict the remaining lifespan of non-pre-stressed
individuals
[53,68,73,101,110,117,119,132,134,146,150
e
e
152,154,155]
. These reporters include components and
targets of the insulin-like/DAF-16 signaling pathway, and
may reflect the differing extent to which worms are expe-
riencing or detecting pathogenic infection
[152]
. Addi-
tional reporters that partially predict remaining lifespan
quantify the expression of miRNAs previously suggested to
influence lifespan. Indeed, quantifying the early-to-mid
adult expression of three miRNAs in individuals predicted
more than 40% of the variation in their remaining lifespan.
Two of these miRNAs may act upstream of the insulin-like
signaling pathway to influence lifespan variation
[150]
.
The other context in which inter-individual variation
has been studied in C. elegans is with respect to variation in
the outcome of mutations. Many mutations are incom-
pletely penetrant, affecting only a subset of isogenic
individuals who carry them. For example, partial loss-
of-function mutations in the maternal transcription factor
SKN-1 only cause defects in intestine development in some
worms. Using single molecule fluorescence in situ
Variation in Gene Expression among
Individuals and its Phenotypic Consequences
Isogenic individuals often show substantial phenotypic
variation, even when they share a common, controlled
environment. This is true of species from microorganisms
to mice, and identifying the causes and consequences of
inter-individual variation presents an important challenge
for systems biology. C. elegans represents an attractive
model for the study of inter-individual variation: labora-
tory strains are isogenic and self-fertilizing, wild-type
animals produce several hundred genetically identical
offspring, the invariant cell lineage means that individual
cells can be identified with confidence, and the small and
transparent embryo allows behaviors and gene expression
to be easily quantified in vivo. As such, a series of
recent
studies have
examined different aspects of
