Interdisciplinary Biotechnology Unit, Aligarh Muslim University (AMU), Aligarh, Uttar Pradesh, 202002, India.
Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi, 110029, India.
Sci Rep. 2020 Jul 24;10(1):12408. doi: 10.1038/s41598-020-68270-1.
The human implantation failure during first trimester leads to spontaneous abortions. Spontaneous abortions are consecutive and occur twice or thrice (with or without prior live births) due to factors which are either maternal or fetal. However, it also constitutes of unknown etiology; known as unexplained recurrent spontaneous abortions (URSA). In this study, the medical terminated human normal early pregnancies (NEP) of the first trimester were taken as control samples, the normal decidual sample whose molecular and epigenetic changes were compared with that of decidua of human URSA subjects. Apoptosis-related genes reported in consecutive recurrent pregnancy loss became the basis for this study. So, in this study, we evaluated the hypothesis that "p53 methylation level through methyltransferases (G9aMT and DNMT1) implicates the fate of embryo towards sustenance or cessation of pregnancy". Further, the interaction between P53, BAX, BCL-2, CASPASE-6, G9aMT, DNMT-1, and methylated p53 expression level(s) during the first trimester of both URSA and NEP are included in this study. The degree of p53 methylation during the first trimester is found to be significant and positively correlated with that of G9aMT (p < 0.05), BCL-2 (p < 0.001), and DNMT1 (p < 0.001) at both transcript and protein level. A significant and negative correlation (with p-value < 0.001) between the degree of p53 methylation during the first trimester and that of the expression level of TUNEL assay (Apoptosis), P53, BAX, and CASPASE-6 are also observed in the present study. A positive correlation between apoptosis and a higher level of p53 expression (which is possibly due to low degree of p53 methylation) is observed both at the transcript and protein level in URSA which is in line with our findings. The analysis performed using structural equation modelling (SEM) further throws light on the causal relationship between sustenance of pregnancy or URSA during the first trimester of a human pregnancy and degree of methylation of p53 which is closely correlated with the interaction between G9aMT, DNMT1, BCL-2, BAX, P53, CASPASE-6, and apoptosis.
人在妊娠早期的着床失败会导致自然流产。自然流产是连续发生的，发生两次或三次（有或没有先前的活产），原因是母体或胎儿的因素。然而，它也构成了未知病因；被称为不明原因的复发性自然流产（URSA）。在这项研究中，我们将人妊娠早期的医学终止正常妊娠（NEP）作为对照样本，比较了与 URSA 患者蜕膜相比，正常蜕膜的分子和表观遗传变化。在连续妊娠丢失中报道的与凋亡相关的基因成为本研究的基础。因此，在这项研究中，我们评估了“通过甲基转移酶（G9aMT 和 DNMT1）使 p53 甲基化水平影响胚胎的命运，是维持妊娠还是终止妊娠”这一假设。此外，本研究还包括了在 URSA 和 NEP 的妊娠早期，p53、BAX、BCL-2、CASPASE-6、G9aMT、DNMT-1 之间的相互作用，以及甲基化 p53 的表达水平。我们发现，在妊娠早期，p53 的甲基化程度与 G9aMT（p<0.05）、BCL-2（p<0.001）和 DNMT1（p<0.001）在转录和蛋白水平上呈显著正相关。在本研究中还观察到，在妊娠早期，p53 甲基化程度与 TUNEL 检测（凋亡）、p53、BAX 和 CASPASE-6 的表达水平之间存在显著的负相关（p 值均<0.001）。在 URSA 中，在转录和蛋白水平上都观察到凋亡与 p53 表达水平的正相关（这可能是由于 p53 甲基化程度较低），这与我们的发现一致。使用结构方程模型（SEM）进行的分析进一步阐明了人类妊娠早期妊娠的维持或 URSA 与 p53 甲基化程度之间的因果关系，p53 甲基化程度与 G9aMT、DNMT1、BCL-2、BAX、p53、CASPASE-6 和凋亡之间的相互作用密切相关。
