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大猪小猪落玉盘

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! A. D7 U3 B" |8 a# p# K8 @Intrauterine growth retardation (IUGR) has been linked to the onset of diseases in adulthood, including type- e1 z9 R3 m+ S8 g
2 diabetes, and has been proposed to result from altered gene regulation patterns due to epigenetic modifications: w; m3 e  {' Q; S
of developmental genes. To determine whether epigenetic modifications may play a role in the development
6 h6 M6 P9 `% Y9 d% q/ L6 {of adult diabetes following IUGR, we used a rodent model of IUGR that expresses lower levels of Pdx1, a
; W+ _# b6 q! K6 D1 B" ^" g# X, i3 Vpancreatic and duodenal homeobox 1 transcription factor critical for β cell function and development, which; @1 _3 a. W- h
develops diabetes in adulthood. We found that expression of Pdx1 was permanently reduced in IUGR β cells
6 n' W# C: D6 o) k0 [4 H" N4 qand underwent epigenetic modifications throughout development. The fetal IUGR state was characterized by
+ u0 r3 D9 A# rloss of USF-1 binding at the proximal promoter of Pdx1, recruitment of the histone deacetylase 1 (HDAC1) and
( L1 X+ u! |! Z' m) f6 D9 K; ]* othe corepressor Sin3A, and deacetylation of histones H3 and H4. Following birth, histone 3 lysine 4 (H3K4)
0 s' i( N3 {8 s: z  l/ Gwas demethylated and histone 3 lysine 9 (H3K9) was methylated. During the neonatal period, these epigenetic5 \) b, }3 s: Z$ t
changes and the reduction in Pdx1 expression could be reversed by HDAC inhibition. After the onset of diabetes
! K0 [  t6 w7 P! Oin adulthood, the CpG island in the proximal promoter was methylated, resulting in permanent silencing' }" O; D0 n! g: U0 x) \% y. W. d
of the Pdx1 locus. These results provide insight into the development of type 2 diabetes following IUGR and we
2 O/ C$ H9 g8 n! c& Qbelieve they are the first to describe the ontogeny of chromatin remodeling in vivo from the fetus to the onset/ y% M. w6 L' ^/ I# s/ [
of disease in adulthood.4 T. o! g4 T: Y% o$ p2 r6 h7 B9 ^' K3 R
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