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Epigenetics from Oocytes to Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Dagnė Daškevičiūtė, Marta Sanchez-Delgado, David Monk
H3K27me3 is a polycomb-based histone modification associated with gene repression49 and can be inherited from the oocyte regulating enhancer function and lineage-specific genes.50 In the mouse zygote, H3K27me3 located in promoter regions in both the maternal and paternal genomes is lost, followed by rapid redistributions during the cleavage stages.50 The rapid erasure throughout the paternal genome is accompanied by selective depletion at maternal promoters. Recently, oocyte-derived, maternal H3K27me3-mediated imprinting has been described in mouse pre-implantation embryos for several genes, including Gab1, Phf17, Sfmbts, and Slc38a4.50 This occurs at DNA unmethylated promoter regions, but is transient, being lost by implantation, reflecting the complementary roles of H3K27me3 and 5mC in regulating imprinting. During human pre-implantation development, the H3K27me3 oocyte and embryonic profiles differ from mice. By the eight-cell cleavage stage, human embryos exhibit complete erasure on both parental genomes,43 consistent with the largely non-existent H3K27me3-mediated, germline 5mC-independent temporal imprinting.51,52 H3K27me3 also appears in intergenic regions, where it is widespread and may be involved in transcriptional repression, compensating for the lack of 5mC and H3K9me3 during reprogramming. This is especially important at repeat-rich sequences such as long terminal repeat (LTR) retrotransposons, which must be properly regulated to avoid recombination, self-duplication, and genome instability. Since 5mC is largely demethylated shortly after fertilization, silencing of LTRs requires a switch from 5mC to repressive histone modifications, including H3K27me3 and H3K9me3.53 Promoters demarked by H3K9me3 are erased at fertilization and re-established at post-implantation stages, indicating that unique sequences and LTRs have different regulatory mechanisms, likely involving ZFP-KAP1 complexes.
Up-regulated miR-155 is associated with poor prognosis in childhood acute lymphoblastic leukemia and promotes cell proliferation targeting ZNF238
Published in Hematology, 2021
Cong Liang, Yu Li, Li-Na Wang, Xiao-Li Zhang, Jie-Si Luo, Chun-Jin Peng, Wen-Yan Tang, Li-Bin Huang, Yan-Lai Tang, Xue-Qun Luo
Computational prediction of human miRNA targets from StarBase suggested that miR-155 can modulate more than 1000 genes (Figure 4(A)). To further explore the underlying mechanism of miR-155 regulatory network, we performed KEGG analysis of these targets of miR-155. The results proposed that miR-155 might participate in cellular mechanisms associated with ALL dysregulation (eg, PI3K-Akt, mTOR, and AMPK) (Figure 4(B)). To further identify a functional miR-155 target, we chosen the genes that were predicted by at least four databases simultaneously. 75 of the putative miR-155 targets met the requirements. Then, we performed correlation analysis of miRNA and target genes in leukemia (p>0.05). Sixteen of the target non-oncogenes in leukemia were significantly correlated with miR-155 (Table 2). Among them, JARID2, PHF17, RREB1, SDCBP and BACH1 had been already demonstrated as the targets of miR-155 in leukemia. Previous studies have proposed that ZNF238 is the novel tumor suppressor in human brain cancer [24], which can drastically decrease proliferation and promote cell death in medulloblastoma and glioblastoma multiforme cells [25]. However, the role of ZNF238 in childhood ALL is unknown. Figure 4(C) shows the predicted binding sites between miR-155 and ZNF238. Dual luciferase reporter assay was performed in HEK-293 T cells (Figure 4(D)). Furthermore, the expression of ZNF238 was inhibited at the protein and mRNA levels in CEM-C1 and MOLT-4 cells transfected with miR-155 mimics, miR-155 inhibitors, and corresponding controls (Figure 4(E,G)). To analyze ZNF238 expression between childhood ALL patients and healthy controls, we chose Coustan-Smith Leukemia dataset in ONCOMINE database, which contains 46 children with T-ALL, 238 children with B- ALL and 4 healthy controls. We found that ZNF238 was significantly reduced in children ALL (Figure 4(H)).