A complex deoxyribonucleic acid looping configuration associated with the silencing of the maternal Igf2 allele.
Alternate interactions between the H19 imprinting control region (ICR) and one of the two Igf2 differentially methylated regions has been proposed as a model regulating the reciprocal imprinting of Igf2 and H19. To study the conformation of this imprint switch, we performed a systematic structural analysis across the 140 kb of the mouse Igf2-H19 region, which includes enhancers located both between the two genes as well as downstream of H19, by using a scanning chromosome conformation capture (3C) technique. Our results suggest that on the active paternal Igf2 allele, the various enhancers have direct access to the Igf2 promoters, whereas the imprinted silent maternal Igf2 allele assumes a complex three-dimensional knotted loop that keeps the enhancers away from the Igf2 promoters and allows them to interact with the H19 promoter. This complex DNA looping of the maternal allele is formed by interactions involving differentially methylated region 1, the ICR, and enhancers. Binding of CTC-binding factor to the maternal, unmethylated ICR in conjunction with the presence of multicomplex components including interchromosomal interactions, create a barrier blocking the access of all enhancers to Igf2, thereby silencing the maternal Igf2. This silencing configuration exists in newborn liver, mouse embryonic fibroblast, and embryonic stem cells and persists during mitosis, conferring a mechanism for epigenetic memory.
Qiu
Xinwen
X
Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.
Vu
Thanh H
TH
Lu
Qiucheng
Q
Ling
Jian Qun
JQ
Li
Tao
T
Hou
Aiju
A
Wang
Shu Kui
SK
Chen
Hui Ling
HL
Hu
Ji Fan
JF
Hoffman
Andrew R
AR
D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D040582:Inheritance Patterns / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009035:Mothers; D009690:Nucleic Acid Conformation; D062085:RNA, Long Noncoding; D023121:RNA, Messenger, Stored / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism
C094335:H19 long non-coding RNA; C513121:IGF2 protein, mouse; D062085:RNA, Long Noncoding; D023121:RNA, Messenger, Stored; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II; D004247:DNA