Transcript j. Biol. Chem

Institute
for Life Sciences
Pregnancy Induced Changes in the Mouse Liver Transcriptome
Leonie R. Grenfell, Samuel P. Hoile, Mark A. Hanson, Karen A. Lillycrop and Graham C. Burdge.
Background
During pregnancy, dramatic metabolic changes occur in response
to the growing fetus. These changes have been particularly
documented in the rat liver which shows an increase in size during
pregnancy (Poo et al., 1939) in response to sex hormones (Griffiths
et al., 1941). Despite this, there has been very little further research
in to how these alterations are initiated and regulated by the
transcriptome. The aim of this study was to characterize changes in
gene expression in the liver in relation to the changing metabolic
phenotype of the mother.
Leptin levels were significantly increased at d14 (p=0.005).
Plasma levels of glucose were found to decrease at d7 before
increasing at d18 (p=0.021). No significant differences were
found in plasma β-Hb levels.
Figure 3. Proportion of genes showing altered gene expression
Altered Gene Expression in Liver
Down-regulated
3902
Methods
Molecules Associated with Altered Gene
Expression
in Relation to Function
4000
Gastrointestinal
disease
3000
2000
Developmental
Disorder
1000
b
c
Energy Intake(KJ) /10g
body weight
30
20
10
a
b
a
a
30
Leptin concentration
throughout pregnancy
Day of Pregnancy
un
ct
io
n
og
i
Small Molecule
Biochemistry
712
18
a
100
Embryonic
Development
577
Total molecules altered within most
significant systems = 3254
Substantial alteration in the gene expression profile was found at
d18 of pregnancy in the liver when compared to non pregnant
controls. 43% of the genes found on the array had more than a 2fold increase or decrease in expression and are associated with
fundamental functions across cell proliferation, metabolism and
fetal development.
Conclusions
These results show that pregnancy induces substantial changes in
the regulation of the hepatic transcriptome. Further work will
test the hypothesis that such transcriptional changes involve
altered epigentic regulation of specific genes
References
Pr
eg
D
18
Pr
eg
D
14
Pr
eg
0
D
7
Pr
eg
D
18
Pr
eg
Pr
eg
D
7
D
14
N
on
Pr
eg
0
ab
Organismal
Survival
1363
Griffiths, M., Marks, H. P., & Young, F. G. (1941). Influence of (Œstrogens and
Androgens on Glycogen Storage in the Fasting Rat. Nature, 147 (3725), 359–359.
Poo, L. J., Lew, W., & Addis, T. (1939). Protein Ananbolism of Organs and Tissues
During Pregnancy and Lactation. j. Biol. Chem, 128, 69–77.
eg
500
b
200
Pr
1000
ab
on
1500
300
N
2000
Concentration of Glucose mg/dl
a
Glucose concentration
throughout pregnancy
Digestive
System Function
Organ Morphology
Total molecules altered within most
significant systems = 3170
Figure 2. Plasma leptin and glucose concentration during
pregnancy.
a
Cell Death
and Survival
1088
D
ay
14
D
ay
7
D
ay
ay
0
18
14
D
ay
7
D
ay
0
ay
D
D
ay
Day of Pregnancy
Most Significant Systems Altered in
Physiological Function
Hepatic
System
Function
Lipid
Metabolism
As expected, significant weight gain was observed between d7 and
d14 (p<0.001), which was sustained until d18 (p<0.001). Food
intake also increased at d14 compared to pre-conception
(p=0.007), reaching a plateau between d14 and d18. Energy intake
increased between conception and d7 (p=0.032) before returning
to non-pregnant levels in late gestation.
a
ca
lF
un
ct
io
n
Ph
ys
nd
ul
ar
a
10
0
2500
io
l
s
se
ea
Molecular
Transport
Day of Pregnancy
Concentration of Leptin pg/ml
Most Significant Systems Altered in Molecular
and Cellular Function
20
0
b
Total molecules altered within most
significant systems = 2251
Cell
Morphology
D
Weight/g
40
a
C
el
lu
la
rF
is
D
d
40
a
Cancer
605
0
an
50
Organismal
injury
613
M
ol
ec
D
Energy intake during pregnancy
is
Weight gain during pregnancy
Most Significant Systems Altered in Disease
and Disorder
Hepatic
System
Disease
or
de
r
Figure 1. Weight gain and energy intake throughout pregnancy
Figure 4. Molecular pathways associated with expression changes
s
Results
No alteration
10288
Total genes represented on array = 18098
Number of associated
molecules
90 day old (n=>6), C57/Blk6 virgin mice maintained on standard
chow were mated and weight gain and 24 hour food intake were
measured weekly. Age matched virgin female mice were used as
non-pregnant controls. Mice were culled at days 7, 14 and 18 of
gestation (d7, d14 and d18) and organs collected. Serum levels of βhydroxybutyrate (β-Hb), leptin and glucose were measured using
colorimetric or ELISA assays. RNA was extracted from liver and
transcriptome analysis carried out on the Illumina MouseRef-8
v2.0 Expression BeadChip.
Up-regulated
3908
Day of Pregnancy
www.southampton.ac.uk/ifls
Acknowledgements