Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis

Zhou, Xin; Shin, Sonyo; He, Chenxi; Zhang, Qiang; Rasband, Matthew N.; Ren, Jiangong; Dai, Congxin; Zorrilla-Veloz, Rocío I.; Shingu, Takashi; Yuan, Liang; Wang, Yunfei; Chen, Yiwen; Lan, Fei; Hu, Jian

doi:10.7554/elife.60467

Cited by 20 publications

(15 citation statements)

References 79 publications

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“…QKI was found to regulate the structural lipid components of myelin, through interaction with the peroxisome proliferator‐activated receptor β–retinoid X receptor α complex, leading to the differential regulation of genes associated with lipid metabolism (Zhou et al, 2020 ). The same group discovered that QKI also regulates cholesterol metabolism in myelinogenesis, again through transcription, in this instance through co‐activation with the transcriptional activator, Sterol regulatory element‐binding protein 2 (Srebp2) (Zhou et al, 2021 ). This work was expanded to show that QKI co‐activates Srebp2‐mediated transcription of cholesterol‐metabolism genes in eye lens cells, where mice deficient in QKI have loss of lens transparency (Shin et al, 2021 ).…”

Section: Structure Of Qki Proteins and Functions I...mentioning

confidence: 99%

The Quaking RNA‐binding proteins as regulators of cell differentiation

2022

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The RNA‐binding protein Quaking (QKI) has emerged as a potent regulator of cellular differentiation in developmental and pathological processes. The QKI gene is itself alternatively spliced to produce three major isoforms, QKI‐5, QKI‐6, and QKI‐7, that possess very distinct functions. Here, we highlight roles of the different QKI isoforms in neuronal, vascular, muscle, and monocyte cell differentiation, and during epithelial–mesenchymal transition in cancer progression. QKI isoforms control cell differentiation through regulating alternative splicing, mRNA stability and translation, with activities in gene transcription now also becoming evident. These diverse functions of the QKI isoforms contribute to their broad influences on RNA metabolism and cellular differentiation. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Development

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Section: Structure Of Qki Proteins and Functions I...mentioning

confidence: 99%

The Quaking RNA‐binding proteins as regulators of cell differentiation

2022

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“…Originally identified as an RNA-binding protein ( 12 ), QKI also binds directly to DNA ( 13 , 14 ), and its RNA/DNA binding activity promotes the transcription of genes involved in lipid metabolism in oligodendrocytes, lens epithelial cells, and microglia ( 13 – 16 ). QKI is mutated or deleted in approximately 34% of human GBMs (30% hemizygous deletions, 2% homozygous deletions, 2% mutations) ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Immune landscape of a genetically engineered murine model of glioma compared with human glioma

Zamler¹,

Shingu²,

Kahn³

et al. 2022

JCI Insight

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Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that were predominantly myeloid cells (e.g., monocytes, macrophages, and microglia), with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found more neutrophils and T and NK cells in the implanted model. Neutrophils and T and NK cells were increased in abundance in samples derived from human high-grade glioma compared with those derived from low-grade glioma. Overall, our data demonstrate that our implanted and spontaneous QPP models recapitulate the immunosuppressive myeloid-dominant nature of the tumor microenvironment of human gliomas. Our model provides a suitable tool for investigating the complex immune compartment of gliomas.

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“…ZNF800 is a zinc finger protein whose molecular functions are poorly studied, yet it is implicated in diseases such as lung cancer (Zhuo et al 2020). In contrast, QKI is a well-studied RBP involved in many RNA-related processes and is known to play a major part in neuronal gene regulation and neuron myelination Chen, Yin, et al 2021;Zhou et al 2021;Shin et al 2021;Åberg et al 2006).…”

Section: Rna-binding Proteins Qki and Znf800 Are Involved In The Regu...mentioning

confidence: 99%

Systematic Identification of Post-Transcriptional Regulatory Modules

Khoroshkin

Buyan

Dodel

et al. 2023

Preprint

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In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored. Here, we performed a systematic annotation of RBP combinatorial interactions via multimodal data integration. We built a large-scale map of RBP protein neighborhoods by generatingin vivoproximity-dependent biotinylation datasets of 50 human RBPs. In parallel, we used CRISPR interference with single-cell readout to capture transcriptomic changes upon RBP knockdowns. By combining these physical and functional interaction readouts, along with the atlas of RBP mRNA targets from eCLIP assays, we generated an integrated map of functional RBP interactions. We then used this map to match RBPs to their context-specific functions and validated the predicted functions biochemically for four RBPs. This study highlights the previously underappreciated scale of the inter-RBP interactions, be it genetic or physical, and is a first step towards a more comprehensive understanding of post-transcriptional regulatory processes and their underlying molecular grammar.

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Qki regulates myelinogenesis through Srebp2-dependent cholesterol biosynthesis

Cited by 20 publications

References 79 publications

The Quaking RNA‐binding proteins as regulators of cell differentiation

The Quaking RNA‐binding proteins as regulators of cell differentiation

Immune landscape of a genetically engineered murine model of glioma compared with human glioma

Systematic Identification of Post-Transcriptional Regulatory Modules

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