Effect for Human Genomic Variation During the BMP4-Induced Conversion From Pluripotent Stem Cells to Trophoblast

Abstract

The role of genomic variation in differentiation is currently not well understood. Here, the genomic variations were determined with the whole-genome sequencing for three pairs of pluripotent stem cell lines and their corresponding BMP4-induced trophoblast cell lines. We identified ∼3,500 single nucleotide variations and ∼4,500 indels by comparing the genome sequenced data between the stem cell lines and the matched BMP4induced trophoblast cell lines and annotated them by integrating the epigenomic and transcriptomic datasets. Relatively, introns enrich more variations. We found ∼45% (42 genes) of the differentially expressed genes in trophoblasts that associate genomic variations. Six variations, located at transcription factor binding sites where H3K4me3 and H3K27ac are enriched in both H1 and H1_BMP4, were identified. The epigenetic status around the genomic variations in H1 was similar to that in H1_BMP4. This means that the variation-associated gene's expression change can not be attributed to epigenetic alteration. The genes associated with the six variations were upregulated in differentiation. We inferred that during the differentiation, an increased in the expression level of the MEF2C gene is due to a genomic variation in chromosomes 5: 88179358 A > G, which is at a binding site of TFs KLF16, NR2C2, and ZNF740 to MEF2C. Allele G shows a higher affinity to the TFs in the induced cells. The increased expression of MEF2C leads to an increased expression of TF MEF2C's target genes, subsequently affecting the differentiation. Although genomic variation should not be a dominant factor in differentiation, we believe that genomic variation could indeed play a role in the differentiation from stem cells into trophoblast.

Omics Approaches to Study Formation and Function of Human Placental Syncytiotrophoblast

“…Furthermore, XAGE2 and KCNQ2 , which were upregulated in KRT7+ cells, exhibited distinct expression patterns in human placenta in situ ( Tsuchida et al, 2020 ). Li et al (2020) used whole-genome sequencing (WGS) along with published transcriptomic and epigenomic datasets to identify 6 genomic variations associated with genes upregulated following BMP4-mediated differentiation of hPSCs. One of these was a single nucleotide variation in the promoter region of MEF2C that increased the binding affinity of TFs to this region.…”

“…One of these was a single nucleotide variation in the promoter region of MEF2C that increased the binding affinity of TFs to this region. This resulted in increased expression of MEF2C and its target genes, thereby promoting trophoblast differentiation ( Li et al, 2020 ). The use of hiPSCs has also been exploited to study patient-specific STB developmental processes.…”

Dynamics of transcriptional and post-transcriptional regulation

“…Finally, we recently proposed a novel approach, INSPEcT-, which, for the first time, enabled us to model the whole set of RNA kinetic rates based on time course RNA-seq datasets [ 3 , 23 ]. INSPEcT- considers the temporal delay between the responses of premature and mature forms proportional to mature RNA half-life, which can thus be estimated.…”

Expression Quantitative Trait Locus Study of Non-Syndromic Cleft Lip with or without Cleft Palate GWAS Variants in Lip Tissues

“…Among some unfamiliar genes in NSCL/P, TAF1B, and ZNF740 are transcription factors, which belong to the TATA-box binding protein-associated factors family and the zinc finger protein family, respectively. They involve in the universal transcription regulation process in cells [ 38 , 39 , 40 ] and play important roles in growth, aging, and responses to abiotic and biotic stresses. Despite their similar functions within their families, their independent roles and interactions with other family members or genes are still largely unveiled.…”