Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes

Abstract

ZC3H11A (zinc finger CCCH domain–containing protein 11A) is a stress-induced mRNA-binding protein required for efficient growth of nuclear-replicating viruses. The cellular functions of ZC3H11A during embryonic development are unknown. Here, we report the generation and phenotypic characterization of Zc3h11a knockout (KO) mice. Heterozygous null Zc3h11a mice were born at the expected frequency without distinguishable phenotypic differences compared with wild-type mice. In contrast, homozygous null Zc3h11a mice were missing, indicating that Zc3h11a is crucial for embryonic viability and survival. Zc3h11a –/– embryos were detected at the expected Mendelian ratios up to late preimplantation stage (E4.5). However, phenotypic characterization at E6.5 revealed degeneration of Zc3h11a –/– embryos, indicating developmental defects around the time of implantation. Transcriptomic analyses documented a dysregulation of glycolysis and fatty acid metabolic pathways in Zc3h11a –/– embryos at E4.5. Proteomic analysis indicated a tight interaction between ZC3H11A and mRNA-export proteins in embryonic stem cells. CLIP-seq analysis demonstrated that ZC3H11A binds a subset of mRNA transcripts that are critical for metabolic regulation of embryonic cells. Furthermore, embryonic stem cells with an induced deletion of Zc3h11a display an impaired differentiation toward epiblast-like cells and impaired mitochondrial membrane potential. Altogether, the results show that ZC3H11A is participating in export and posttranscriptional regulation of selected mRNA transcripts required to maintain metabolic processes in embryonic cells. While ZC3H11A is essential for the viability of the early mouse embryo, inactivation of Zc3h11a expression in adult tissues using a conditional KO did not lead to obvious phenotypic defects.

Quantitative proteomics reveals the dynamic proteome landscape of zebrafish embryos during the maternal-to-zygotic transition

“…Proteins in this cluster are also involved in mRNA binding, export from nucleus, and posttranscriptional regulation, i.e., Zc3h11a. 84 This cluster also contains proteins related to early organogenesis, for example, Ttf2 contributes to thyroid development. 85 The functional enrichment data demonstrates that proteins in this cluster are significantly involved in DNA repair, ribosome biogenesis, mRNA binding and export, and methylation.…”

A comprehensive analysis of spermatozoal RNA elements in idiopathic infertile males undergoing fertility treatment

“…CCDC9 was also previously identified as a novel candidate gene of severe asthenozoospermia and has been reported to regulate sperm motility and spermiogenesis 53 , 54 . Moreover, CCDC9 has also previously been associated with ZC3H11A, an mRNA binding protein that is required for mouse embryo development to the peri-implantation stage 55 .…”

The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts

“…ZC3H11A is an RNA-binding protein with three uncharacterized CCCH-type zinc finger motifs (ZFM) present at the N-terminus of the protein ( 3 ). Several studies have shown that ZC3H11A is a subunit of the Transcription-Export (TREX) complex responsible for the nuclear mRNA export ( 4 , 5 , 6 , 7 , 8 ). TREX is a multiprotein complex containing the hexameric core THO complex (THOC1, THOC2, THOC3, THOC5, THOC6, and THOC7), which in turn associates with several subunits including ZC3H11A ( 9 ).…”

“…Two very recent studies have further shed light on ZC3H11A functions. First, it has been shown that ZC3H11A is crucial for the viability and survival of mouse embryos ( 8 ). Notably, genetic characterization of Zc3h11a −/− mice embryos revealed dysregulation of the fatty acid and glycolysis pathways ( 8 ).…”

“…First, it has been shown that ZC3H11A is crucial for the viability and survival of mouse embryos ( 8 ). Notably, genetic characterization of Zc3h11a −/− mice embryos revealed dysregulation of the fatty acid and glycolysis pathways ( 8 ). Second, the human ZC3H11A protein can suppress NF-κB signaling, thereby controlling the expression of several interferon-stimulated genes in HeLa cells ( 21 ).…”