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. ~9 x  j0 g4 b4 u; b% Z$ G# }. jIntrauterine growth retardation (IUGR) has been linked to the onset of diseases in adulthood, including type$ b$ I4 P) t6 n) T2 L6 _- L
2 diabetes, and has been proposed to result from altered gene regulation patterns due to epigenetic modifications5 w; f/ e5 i2 J3 z9 M* e7 J2 K
of developmental genes. To determine whether epigenetic modifications may play a role in the development
) `5 I2 v) n0 @( U/ N4 o, Yof adult diabetes following IUGR, we used a rodent model of IUGR that expresses lower levels of Pdx1, a
/ {- s! D6 I4 x! W1 X# Jpancreatic and duodenal homeobox 1 transcription factor critical for β cell function and development, which9 O$ _2 Z' T3 i: `
develops diabetes in adulthood. We found that expression of Pdx1 was permanently reduced in IUGR β cells: n# l2 b9 X3 @& Y7 |* M! i
and underwent epigenetic modifications throughout development. The fetal IUGR state was characterized by- E$ P: H1 Z$ x( n
loss of USF-1 binding at the proximal promoter of Pdx1, recruitment of the histone deacetylase 1 (HDAC1) and
% \" M1 F! v9 x, m2 ~6 `0 i9 Mthe corepressor Sin3A, and deacetylation of histones H3 and H4. Following birth, histone 3 lysine 4 (H3K4)
" E/ z' {7 G. H8 a; ^2 ~was demethylated and histone 3 lysine 9 (H3K9) was methylated. During the neonatal period, these epigenetic
+ @9 }; @# n/ h% Schanges and the reduction in Pdx1 expression could be reversed by HDAC inhibition. After the onset of diabetes
: H0 F  D) c* Q6 J% {) `3 Fin adulthood, the CpG island in the proximal promoter was methylated, resulting in permanent silencing7 i" ~9 z: K6 b& t
of the Pdx1 locus. These results provide insight into the development of type 2 diabetes following IUGR and we* ]; ?: e! n+ ]
believe they are the first to describe the ontogeny of chromatin remodeling in vivo from the fetus to the onset
% ?% b% u1 w5 G% {& n+ n+ wof disease in adulthood.
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