Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses

Abstract

Epigenetic mechanisms such as genomic imprinting have a fundamental role in embryo and fetal development. Hence, we here studied expression levels of epigenetic modifiers and imprinted genes in cases of ididopathic spontaneous abortion (SA). Thirty-five placental samples and 35 matched fetal tissues from second trimester SA were analysed; including 16 controls (placental and fetal infections as the known cause of spontaneous abortion) and 19 idiopathic SA cases. Transcript levels of epigenetic regulators and imprinted genes were measured by qRT-PCR and methylation at imprinted genes was studied by bisulfite genomic sequencing and MS-MLPA. Global DNA hydroxymethylation (5-hmC) levels were measured by an ELISA-based assay. We observed an upregulation of TET2 and TET3 in placental samples from idiopathic SA cases; however, no significant difference in global 5-hmC levels was observed. On the contrary, in fetal tissues, TET3 was markedly downregulated in idiopathic SA, showing an opposite trend to that observed in placental tissue. IGF2 and CDKN1C were upregulated and MEST downregulated in placentas from idiopathic SA cases; concordantly, IGF2 was also upregulated in fetal tissues from idiopathic SA cases. Although not reaching statistical significance, an increase in methylation levels of MEST, KvDMR1 and H19 DMRs was observed in idiopathic SA cases, concordantly with the observed changes in expression. Our study reveals, for the first time, deregulation of epigenetic modifiers and imprinted genes in both placental and fetal tissues from idiopathic SA cases in the second trimester of pregnancy, indicating a critical role during pregnancy.

Long non‑coding RNA H19 regulates Bcl‑2, Bax and phospholipid hydroperoxide glutathione peroxidase expression in spontaneous abortion

“…SA is the most frequently occurring pregnancy disorder and is a serious threat to women's health (23). SA has been reported to be associated with several risk factors, including endocrine disorders, anatomic deformation, immunodeficiency and chromosomal abnormalities (24)(25)(26)(27).…”

Variants in Maternal Effect Genes and Relaxed Imprinting Control in a Special Placental Mesenchymal Dysplasia Case with Mild Trophoblast Hyperplasia

“…We compared the methylation levels of DMRs between abnormal cystic placenta and adjacent normal control placenta tissues, as well as mixed normal placentae tissues from independent pregnancies with female babied of the same gestation week. We also cross reference to the published DMR patterns in human placenta [ 65 , 66 , 67 , 68 , 69 ]. Most of the examined regions had normal methylation patterns in both the defective cystic placenta regions and adjacent morphologically normal placental tissues.…”

Nutrients and Mother’s Diet in the Epigenetic Regulation of Placenta

“…La metilación del ADN ha sido desde el inicio la modificación epigenética más estudiada y está asociada al silenciamiento o inhibición génica cuando ocurre en la región promotora de los genes [14,24].…”

“…Se ha observado que la metilación generalmente ocurre a nivel de los dinucleótidos CpG y no es más que la adición de un grupo metilo al quinto carbono de una citosina, originando una 5-metilcitosina (5-mC), todo este proceso se da mediante la acción de enzimas catalizadoras, a las cuales se las ha denominado ADN metiltransferasas (ADNMT) [14,24,25]. Profundizando un poco más acerca de las ADNMT, existen subtipos, denominados ADNMT1, ADNMT3A, ADNMT3B, recientemente se descubrieron otras enzimas que se cree oxidan la 5-mC, provocando la desmetilación del ADN, los subtipos reconocidos son TET1, TET2, TET3 [24][25][26].…”

“…La existencia de errores en la impresión de los genes puede ser causados por interrupciones epigenéticas que pueden dar como producto la presencia de diferentes fenotipos y dar paso a entidades nosológicas como la restricción del crecimiento fetal, abortos espontáneos, maduración acelerada de la placenta, nacimientos prematuros e incluso se vincula con la presentación de preeclampsia [14,15,24,27].…”