Tip110 Deletion Impaired Embryonic and Stem Cell Development Involving Downregulation of Stem Cell Factors Nanog, Oct4, and Sox2

Abstract

HIV-1 Tat-interacting protein of 110 kDa, Tip110, plays important roles in multiple biological processes. In this study, we aimed to characterize the function of Tip110 in embryonic development. Transgenic mice lacking expression of a functional Tip110 gene (Tip110 -/-) died postimplantation, and Tip110 -/-embryos exhibited developmental arrest between 8.5 and 9.5 days post coitum. However, in vitro cultures of Tip110 -/-embryos showed that Tip110 loss did not impair embryo growth from the zygote to the blastocyst. Extended in vitro cultures of Tip110 -/-blastocysts showed that Tip110 loss impaired both blastocyst outgrowth and self-renewal and survival of blastocyst-derived embryonic stem cells. Microarray analysis of Tip110 -/-embryonic stem cells revealed that Tip110 loss altered differentiation, pluripotency, and cycling of embryonic stem cells and was associated with downregulation of several major stem cell factors including Nanog, Oct4, and Sox2 through a complex network of signaling pathways. Taken together, these findings document for the first time the lethal effects of complete loss of Tip110 on mammalian embryonic development and suggest that Tip110 is an important regulator of not only embryonic development but also stem cell factors. STEM CELLS 2017;35:1674-1686 SIGNIFICANCE STATEMENTHIV-1 Tat-interacting protein of 110 kDa (Tip110) is a nuclear protein with several important biological functions including pre-mRNA alternate splicing and gene transcription. In this study, we determined its role in mammalian embryonic development and the underlying molecular mechanisms. Using the conditional knockout strategy, we showed that loss of the Tip110 gene impaired embryonic development and stem cell pluripotency, self-renewal and survival. We further demonstrated that Tip110 deletion altered expression of stem cell factors such as Nanog, Oct4, and Sox2 in mouse embryonic stem cells through a complex gene network. These findings represent significant advances in our understanding of the biological function of Tip110 and suggest that Tip110 is important for embryonic development and regulation of stem cell factor expression.

Implications of the Wilms’ Tumor Suppressor Wt1 in Cardiomyocyte Differentiation

“…Interestingly, this transient and moderate Wt1 overexpression reduced phenotypical cardiomyocyte differentiation, i.e., the percentage of beating clones throughout the observation period. At the onset of differentiation, signaling pathways regulating pluripotency of mESCs are inhibited through downregulation of stem cell genes, such as Sox2, Oct4, and Nanog [ 89 ]. This corresponds to our findings with significant downregulation of these genes at day 3 of differentiation when the first clones started beating.…”

Tip110 Expression Facilitates the Release of HEXIM1 and pTEFb from the 7SK Ribonucleoprotein Complex Involving Regulation of the Intracellular Redox Level

“…Thus, intramolecular and intermolecular disulfide bond formation between any two cysteine residues of HEXIM1 could also contribute to HEXIM1 dimerization and oligomerization. In separate transcriptomics studies, we have shown that Tip110 knockdown and knockout negatively regulated the glutathione metabolic pathway [ 45 , 46 ]. Both mRNA of glutathione reductase (GSR) and glutathione synthetase (GSS), two major enzymes in the glutathione metabolic pathway were found to be 4 times and 2 times lower, respectively in Tip110 knockout embryonic stem cells than those in the Wt counterparts ( Fig.…”

Molecular Signatures and Networks of Cardiomyocyte Differentiation in Humans and Mice

“…At the onset of differentiation, the signaling pathway regulating pluripotency of hESCs and mESCs is inhibited with the repression of pluripotency genes such as Nanog , Sox2 , and Oct4. 43 Both the Wnt and TGF-β signaling pathways have also been extensively studied for their roles in controlling fate commitment when ESCs start to differentiate into MES. 44 , 45 Similarly, the pathways of DEGs involved in transition from CP to CM are both associated with heart function and related diseases.…”