title: Alteration of Delta-like ligand 1 and Notch 1 receptor in various placental disorders with special reference to early onset preeclampsia.
abstract: Notch signaling pathway has been shown to be dysregulated in placentas with preeclampsia, but there has been a lack of studies on methylation of Notch family genes in this disorder. We therefore executed methylation-specific polymerase chain reaction and immunostaining for Notch 1 receptor and the activating ligand, Delta-like (DLL) 1, with placental tissues from cases of preeclampsia (early onset, n = 18; late-onset, n = 19) and other placental disorders, including maternal complications such as diabetes mellitus and collagen disease (n = 10), fetal growth restriction (n = 17), fetal anomaly (n = 23), preterm birth (n = 15), miscarriage (n = 25), and hydatidiform moles (n = 9) as well as term births (n = 12). The frequency of DLL1 methylation was higher in early onset preeclamptic placentas (61%) than the other subjects (0%-36%; P ≤ .016). Appreciable samples (36%) of miscarriage also represented DLL1 methylation. None of the samples studied showed Notch 1 methylation. On gestational period-matched analysis, the rate of DLL1 methylation was higher in early onset preeclampsia (83.3%) than preterm birth (13.3%; P < .001), with no significant differences in clinical backgrounds between the two. In this analysis, increase of syncytial knots and accelerated villous maturation were most prominent in DLL1-methylated placentas with early onset preeclampsia. Notch 1 and DLL1 expressions in villous trophoblasts and endothelial cells were significantly lower in early onset preeclamptic placentas as compared with preterm birth controls. In conclusion, altered Notch signaling via methylation of DLL1 is likely involved in possible disease-related mechanisms of early onset preeclampsia. Alternatively, DLL1 methylation in early onset preeclampsia could be a manifestation of a lack of placental maturation, similar to miscarriage.
authors.affiliation: Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Human Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: yshima@juntendo.ac.jp.
authors.forename: Yota
authors.initials: Y
authors.lastname: Shimanuki
authors.affiliation: Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga, Tochigi 321-0293, Japan. Electronic address: hmitomi@dokkyomed.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: yfuku@med.juntendo.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fukumura
authors.affiliation: Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: shintaro@juntendo.ac.jp.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Makino
authors.affiliation: Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: a-itakur@juntendo.ac.jp.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Itakura
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: tyao@juntendo.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.affiliation: Department of Obstetrics and Gynecology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: stakeda@juntendo.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takeda
mesh_terms: D000328:Adult; D002135:Calcium-Binding Proteins; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D010922:Placenta Diseases / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D051881:Receptor, Notch1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: DLL1; Methylation; Notch signaling; Placenta; Preeclampsia