| 1. |
- Xu, An, et al.
(author)
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Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.
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| 2. |
- Lee, Dung-Fang, et al.
(author)
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Regulation of embryonic and induced pluripotency by aurora kinase-p53 signaling.
- 2012
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In: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 11:2
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Journal article (peer-reviewed)abstract
- Many signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming.
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| 3. |
- Qu, Yanhua, 1974-, et al.
(author)
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Ground tit genome reveals avian adaptation to living at high altitudes in the Tibetan plateau.
- 2013
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 4, s. 2071-
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Journal article (peer-reviewed)abstract
- The ground tit (Parus humilis) is endemic to the Tibetan plateau. It is a member of family Paridae but it was long thought to be related to the ground jays because of their morphological similarities. Here we present the ground tit's genome and re-sequence two tits and one ground jay, to clarify this controversially taxonomic status and uncover its genetic adaptations to the Tibetan plateau. Our results show that ground tit groups with two tits and it diverges from them between 7.7 and 9.9 Mya. Compared with other avian genomes, ground tit shows expansion in genes linked to energy metabolism and contractions in genes involved in immune and olfactory perception. We also found positively selected and rapidly evolving genes in hypoxia response and skeletal development. These results indicated that ground tit evolves basic strategies and 'tit-to-jay' change for coping with the life in an extreme environment.
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| 4. |
- Zhao, Ruiying, et al.
(author)
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An improved estimate of soil carbon pool and carbon fluxes in the Qinghai-Tibetan grasslands using data assimilation with an ecosystem biogeochemical model
- 2023
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In: Geoderma. - : Elsevier BV. - 0016-7061. ; 430
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Journal article (peer-reviewed)abstract
- The accurate estimation of soil carbon (C) pool and fluxes is a prerequisite to better understand the terrestrial C feedback to climate change. However, recent studies showed considerable uncertainties in soil C estimates. To provide a reliable C estimate in the grasslands of the Qinghai-Tibet Plateau (QTP), we calibrated key parameters in a process-based ecosystem model (the CENTURY model) through data assimilation based on 570 soil samples and 21 sites of eddy covariance measurements. Two assimilating strategies (Opt1 – assimilating C pool observations; Opt2 –assimilating both C pool and C flux) were examined. Compared to default parameterization, our results showed both Opt1 and Opt2 improved the soil organic carbon density (SOCD) estimation, with R2 increasing from 0.59 to 0.75 and 0.73, respectively. Opt2 was superior to Opt1 in constraint of parameters dominating aboveground processes and yield a better estimation of net ecosystem production (NEP). Based on different parameterization, the spatial variability of SOCD and NEP across the QTP grassland were generated. Both Opt1 and Opt2 ameliorated the overestimation of SOCD by the default model, estimating a total soil C of 6.63 Pg and 6.48 Pg C for the topsoil (0–30 cm) of the QTP grasslands, respectively. Opt2 showed lower uncertainties in the NEP estimation and predicted a net sink of 14.33 Tg C annually. Compared with existing datasets, our study provided a more reliable estimation of carbon storage and fluxes in the QTP grassland with the calibrated ecosystem model. The results highlight that data assimilation with multiple observational data sets is promising to constrain process-based ecosystem models and increase the robustness of model predictions for terrestrial C cycle feedback to future climate change.
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