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    Home > Active Ingredient News > Antitumor Therapy > Nature: A new carcinogenic mechanism, phase separation drives abnormal chromatin to form loops, and promotes cancer development

    Nature: A new carcinogenic mechanism, phase separation drives abnormal chromatin to form loops, and promotes cancer development

    • Last Update: 2021-07-31
    • Source: Internet
    • Author: User
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    The development of cancer is closely related to genetic abnormalities that target the intrinsic disordered regions (IDR) of proteins
    .


    IDRs in various proteins (including transcription factors, chromatin regulators, and RNA binding proteins) form aggregates through liquid-liquid phase separation (LLPS), affecting countless biological processes from organelle formation and stimulation of tolerance to gene transcription


    The so-called liquid-liquid phase separation (LLPS) refers to the process of fusing two unrelated gene mutations
    .


    This process occurs in the cell nucleus and can form domains with various physical properties, which can promote the occurrence and development of cancer, such as acute leukemia


    On June 23, 2021, the Gang Greg Wang team of the University of North Carolina at Chapel Hill and Nature published a research paper titled: Phase separation drives aberrant chromatin looping and cancer development
    .

    Phase separation drives aberrant chromatin looping and cancer development

    This study proved that phase separation is the driving factor of cancer formation.
    Cancers obtain mutations through phase separation to establish oncogenic transcription factor aggregates, which at the same time enhance their genome targeting and induce abnormal three-dimensional chromatin structure during tumor transformation.
    Formed
    .


    This study is one of the first to link phase separation with the formation of cancer


    NUP98-HOXA9 contains two protein motifs and a binding sequence
    .


    In order to study the role of NUP98-IDR in the occurrence of leukemia, the research team mainly used NUP98-HOXA9 (N-IDRWT/A9) with the binding sequence knocked out


    They found that N-IDRWT/A9 is sensitive to 1,6-hexanediol (a chemical substance used to destroy phase-phase separation aggregates)
    .


    The purified NUP98-IDR (N-IDR) protein forms a liquid aggregate in vitro


    In order to further evaluate the importance of the concentration dependence and multivalence of FG repeats on the formation of aggregates, the research team prepared recombinant N-IDR proteins containing different numbers of FG repeats
    .


    They found that N-IDR contains 38 or 36 FG droplets formed repeatedly in a concentration-dependent manner, while those containing 27 or 11 FG cannot be phase separated


    NUP98-HOXA9 binds to DNA through the homology domain, leading to gene disorders in the development of leukemia
    .


    Next, the research team chromatin immunization to assess the impact of the phase separation IDR mediated targeting NUP98-HOXA9 chromatin precipitation and high-throughput sequencing


    immunity

    The results show that N-IDRWT/A9 has a significantly enhanced genome occupancy, regardless of the peak subclass defined by unsupervised clustering
    .


    In addition, the wide and dense super-enhancer-like peaks are unique to N-IDRWT/A9, and are enriched in leukemia-related genes during development


    In order to further evaluate the role of IDR-induced LLPS in chimeric chromatin targeting, they used genetic and pharmacological methods to prove the causal role of IDR-mediated LLPS in enhancing the targeting of chimeric transcription factors.
    Especially those seen at the super-enhancer peaks
    .
    It shows that IDR enhances the genome binding of the fusion and enhances the activation of target genes
    .

    To test the ability of NUP98–HOXA9 to form chromatin cycles through LLPS, the research team generated a Hi-C profile of cells expressing N-IDRWT/A9 or N-IDRFS/A9, revealing the high correlation between DNA cycles and replication
    .

    In order to determine the effect of N-IDRWT/A9 on Hi-C contact frequency, they gathered the 500 most intense N-IDRWT/A9-occupied sites in N-IDRWT/A9- and N-IDRFS/A9 expressing cells.
    Interaction count
    .
    The results show that the N-IDRWT/A9 cycle is formed in a way that is basically independent of CTCF, which is consistent with the phase separation drive mechanism
    .
    In addition, the N-IDRWT/A9 specific cycle reconnects the connection between the enhancer and the target gene, supporting the idea that the IDR of the fusion transcription factor induces DNA circulation between the super-enhancer-like target and the oncogene through phase separation
    .

    In summary, the study found that the LLPS active IDR contained in NUP98-HOXA9 is essential for the occurrence of leukemia and the activation of oncogene expression programs
    .
    These effects are mediated by the ability of IDR: 1) to enhance the binding of transcription factors to genomic targets; 2) to promote long-distance circulation between enhancers and oncogene promoters
    .

    This study provides principle evidence for a cancer-causing mutation that promotes LLPS-driven transcription factor binding and 3D chromatin reorganization during tumor transformation
    .
    Since IDR-containing LLPS active molecules are related to a wide range of cancers, the mechanism elucidated by this study can also explain other types of cancers
    .

    Original source:

    Original source:

    Ahn, JH, Davis, ES, Daugird, TA et al.
    Phase separation drives aberrant chromatin looping and cancer development.
    Nature (2021).
    https://doi.
    org/10.
    1038/s41586-021-03662-5.

    Phase separation drives aberrant chromatin looping and cancer development.
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