m.schreuder has documented that he has no relevant ... has documented that he has no relevant...
TRANSCRIPT
M.Schreuder has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.
Role of epigenetics in the development of CAKUT
Michiel SchreuderPediatric Nephrologist4 September 2015
Epigenetics – a definition
“The term epigenetics refers to
heritable changes in gene expression
(active versus inactive genes) that
does not involve changes to the underlying DNA
sequence;
a change in phenotype without a change in
genotype.”
Epigenetics – an example
• Temperature-dependent sex determination
• Based on variable enzyme activity in gonads
PLoS One 2013;8:e63599
Epigenetics
• DNA = identical• Gene = active vs. inactive
“readability”
• Epigenetic mechanisms:• DNA methylation• Histone modification• RNA silencing
Epigenetics
• DNA = identical• Gene = active vs. inactive
“readability”
• Epigenetic mechanisms:• DNA methylation• Histone modification• RNA silencing• non coding RNA (ncRNA)• micro RNA (miRNA)
Epigenetics – an example
• Temperature-dependent sex determination
• Based on variable enzyme activity in gonads
• Based on different DNA methylation levels
PLoS One 2013;8:e63599
Unilateral renal agenesis in 1 of twins
• Copy number variations: no
• SNPs: no
• DNA methylation: 514 different regions
potential explanation?
AJKD 2014;64:119-22
Hypoplasia = low nephron number
• Uteroplacental insufficiency• Steroid exposure• Malnutrition• Protein restriction• Alcohol• Smoking• …
Kidney Int 2003;63:2118
Hypoplasia = low nephron number
• Uteroplacental insufficiency• Steroid exposure• Malnutrition• Protein restriction• Alcohol• Smoking• …
Kidney Int 2003;63:2118
~250,000 glom/kg
Cause of low nephron number
methylation of p53 promotor
Bax expression
apoptosis
nephron number
AJP Reg Integr Comp 2003;285:R962-70
Transgenerational effect - IUGR
Reprod Fertil Dev 2014;26:1032-43
Syst
olic
blo
od
pre
ssu
re(m
mH
g)
Transgenerational effect - Dutch famine
BJOG 2013;120:548-53
• Adult offspring (F2) of prenatally exposed F1 fathershigher weights and BMIs
• Adult offspring (F2) of prenatally exposed F1 mothersno effect
Epigenetics in CAKUT
• Limited data
• May lead to new insight in pathways
• May explain laterality
• May provide options towards modification