Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)

Abstract

Intrauterine growth restriction (IUGR) is a serious pathological complication associated with compromised fetal development during pregnancy. The aim of the study was to broaden knowledge about the transcriptomic complexity of the human placenta by identifying genes potentially involved in IUGR pathophysiology. RNA-Seq data were used to profile protein-coding genes, detect alternative splicing events (AS), single nucleotide variant (SNV) calling, and RNA editing sites prediction in IUGR-affected placental transcriptome. The applied methodology enabled detection of 37,501 transcriptionally active regions and the selection of 28 differentially-expressed genes (DEGs), among them 10 were upregulated and 18 downregulated in IUGR-affected placentas. Functional enrichment annotation indicated that most of the DEGs were implicated in the processes of inflammation and immune disorders related to IUGR and preeclampsia. Additionally, we revealed that some genes (S100A13, GPR126, CTRP1, and TFPI) involved in the alternation of splicing events were mainly implicated in angiogenic-related processes. Significant SNVs were overlapped with 6533 transcripts and assigned to 2386 coding sequence (CDS), 1528 introns, 345 5’ untranslated region (UTR), 1260 3’UTR, 918 non-coding RNA (ncRNA), and 10 intergenic regions. Within CDS regions, 543 missense substitutions with functional effects were recognized. Two known mutations (rs4575, synonymous; rs3817, on the downstream region) were detected within the range of AS and DEG candidates: PA28β and PINLYP, respectively. Novel genes that are dysregulated in IUGR were detected in the current research. Investigating genes underlying the IUGR is crucial for identification of mechanisms regulating placental development during a complicated pregnancy.

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

“…The complex is important for early embryo development and preimplantation in pigs and mice 107,108 . ARPC2 expression has been identified in the BeWo trophoblastic cell line used to investigate placental function 109 and is subject to RNA editing in placentas associated with intrauterine growth restriction/small for gestational age (SGA) 110 . Overall, genes associated with the variant rs10932774 ( PNKD, TMBIM1 and ARPC2 ) show long-term evolutionary conservation consistent with a signature of balancing selection and prior research suggests links to pregnancy through a variety of mechanisms.…”

Insights into the skin of caecilian amphibians from gene expression profiles

“…Three up-regulated caecilian skin sequences, dlx3 (also up-regulated in human skin) , fam26d (family with sequence similarity 26 member D), and adgrg6 (adhesion G-protein coupled receptor G6) are also up-regulated in the human placenta, the organ that provide nutrients to eutherian foetuses [ 39 – 41 ]. During skin feeding in caecilians, maternal epidermis is nutritionally enriched (hypertrophied and lipidified) and the stratum corneum is episodically removed by hatchlings with the help of a specialized vernal dentition, requiring repeated rematuration of the outer layers of the epidermis [ 19 , 20 ].…”

Current approaches and developments in transcript profiling of the human placenta

“…This review considers 17 datasets representing a total of 721 placentas of which 26% were either from SGA- or IUGR-affected pregnancies ( Table II: IUGR/SGA). Most placental transcriptome studies utilized only the criterion of SGA ( McCarthy et al , 2007 ; Sabri et al , 2014 ; Sober et al , 2015 ; Deyssenroth et al , 2017 ; Verheecke et al , 2018 ; Gibbs et al , 2019 ), while some studies excluded those who may be healthy and constitutionally small, by including an additional criterion of a small abdominal circumference below the fifth centile ( Guo et al , 2013 ; Madeleneau et al , 2015 ) or ultrasound findings of abnormal uteroplacental blood flow indicative of placental insufficiency ( Roh et al , 2005 ; Sitras et al , 2009a ; Struwe et al , 2010 ; Nishizawa et al , 2011 ; Dunk et al , 2012 ; Majewska et al , 2019 ). However, while some of these IUGR cases may be explained by maternal smoking, pre-eclampsia or chemotherapy during pregnancy ( Sitras et al , 2009a ; Dunk et al , 2012 ; Verheecke et al , 2018 ), a considerable number of cases have no specific identifiable underlying cause and are termed idiopathic ( Nishizawa et al , 2011 ).…”

“…Dysregulated expression of genes involved in the processes of placental growth signalling, mitochondrial respiration and a hypoxic response was observed in multiple IUGR studies ( Roh et al , 2005 ; McCarthy et al , 2007 ; Struwe et al , 2010 ; Guo et al , 2013 ; Sabri et al , 2014 ; Madeleneau et al , 2015 ; Deyssenroth et al , 2017 ; Verheecke et al , 2018 ). Several studies also demonstrated a substantial overlap between pre-eclampsia and normotensive growth restriction, encompassing genes involved in the molecular processes of placental angiogenesis and immune regulation ( Sitras et al , 2009a ; Nishizawa et al , 2011 ; Dunk et al , 2012 ; Guo et al , 2013 ; Sober et al , 2015 ; Gibbs et al , 2019 ; Majewska et al , 2019 ). Additional research to increase understanding of placental function in growth-compromised pregnancies could improve diagnosis and management of cases.…”