Dataset Information

Reprogramming of m⁶A epitranscriptome is crucial for shaping of transcriptome and proteome in response to hypoxia.

ABSTRACT: Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m⁶A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m⁶A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m⁶A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m⁶A readers were systematically down-regulated. Transcriptome-wide analysis of m⁶A revealed a drastic reprogramming of m⁶A epitranscriptome during cellular hypoxia. Integration of m⁶A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m⁶A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m⁶A eraser, ALKBH5, under hypoxic condition, demonstrating that m⁶A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m⁶A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia.

SUBMITTER: Wang YJ

PROVIDER: S-EPMC7834094 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Reprogramming of m6A epitranscriptome is crucial for shaping of transcriptome and proteome in response to hypoxia.

Wang Yan-Jie YJ Yang Bing B Lai Qiao Q Shi Jun-Fang JF Peng Jiang-Yun JY Zhang Yin Y Hu Kai-Shun KS Li Ya-Qing YQ Peng Jing-Wen JW Yang Zhi-Zhi ZZ Li Yao-Ting YT Pan Yue Y Koeffler H Phillip HP Liao Jian-You JY Yin Dong D

RNA biology 20200818 1

Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m6A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m6A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m6</su ...[more]

PMID: 32746693

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Project description:Our prior study (Tarasov et al., 2022) discovered that numerous adaptive mechanisms emerge in response to cardiac-specific overexpression of adenylyl cyclase type 8 (TGAC8) which included overexpression of a large number of proteins. Here, we conducted an unbiased phosphoproteomics analysis in order to determine the role of altered protein phosphorylation in the adaptive heart performance and protection profile of adult TGAC8 left ventricle (LV) at 3-4 months of age, and integrated the phosphoproteome with transcriptome and proteome. Based on differentially regulated phosphoproteins by genotype, numerous stress-response pathways within reprogrammed TGAC8 LV, including PKA, PI3K, and AMPK signaling pathways, predicted upstream regulators (e.g. PDPK1, PAK1, and PTK2B), and downstream functions (e.g. cell viability, protein quality control), and metabolism were enriched. In addition to PKA, numerous other kinases and phosphatases were hyper-phosphorylated in TGAC8 vs. WT. Hyper-phosphorylated transcriptional factors in TGAC8 were associated with increased mRNA transcription, immune responses, and metabolic pathways. Combination of the phosphoproteome with its proteome and with the previously published TGAC8 transcriptome enabled the elucidation of cardiac performance and adaptive protection profiles coordinately regulated at post-translational modification (PTM) (phosphorylation), translational, and transcriptional levels. Many stress-response signaling pathways, i.e., PI3K/AKT, ERK/MAPK, and ubiquitin labeling, were consistently enriched and activated in the TGAC8 LV at transcriptional, translational, and PTM levels. Thus, reprogramming of the cardiac phosphoproteome, proteome, and transcriptome confers resilience to chronic adenylyl cyclase-driven stress. We identified numerous pathways/function predictions via gene sets, phosphopeptides, and phosphoproteins, which may point to potential novel therapeutic targets to enhance heart adaptivity, maintaining heart performance while avoiding cardiac dysfunction.

Dataset Information

Reprogramming of m⁶A epitranscriptome is crucial for shaping of transcriptome and proteome in response to hypoxia.

Publications

Reprogramming of m<sup>6</sup>A epitranscriptome is crucial for shaping of transcriptome and proteome in response to hypoxia.

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