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    Home > Biochemistry News > Biotechnology News > Chinese and foreign scholars NAR published a paper: Non-coding regulatory elements can stabilize the three-dimensional structure of chromatin

    Chinese and foreign scholars NAR published a paper: Non-coding regulatory elements can stabilize the three-dimensional structure of chromatin

    • Last Update: 2022-05-15
    • Source: Internet
    • Author: User
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    In the non-coding sequences of the human genome, promoters and enhancers are important functional elements for regulating gene expression
    .
    In most cases, activated enhancers interact directly with proximal promoters

    .
    At the same time, there are also some enhancers that can interact with remote promoters in linear genomes through chromatin looping, protein oligomerization, and RNA polymerase II binding enhancers to track along chromatin to play regulatory functions.
    Long-range interactions with promoters demonstrate that regulatory element activity can affect three-dimensional chromatin structure

    .
    In recent years, more and more studies have shown that the interaction between enhancers and promoters is crucial for the formation of specific three-dimensional spatial structures.
    For example, transcription factors and polymerases are not uniformly distributed in the nucleus, but tend to cluster in transcriptionally active or stained regions.
    Dense regions of chromatin; transcriptional processes such as transcription elongation can also affect chromatin structure

    .
    Whether these spatially clustered and transcriptionally active regulatory elements maintain large-scale chromatin structure has not been systematically investigated

    .

    On April 7, 2022, Wei Wensheng's group from Peking University and Wang Wei's group from University of California, San Diego (UCSD) jointly published a research titled " Regulatory elements can be essential for maintaining broad chromatin organization and cell viability " at Nucleic Acids Research In this paper, based on the EpiTensor algorithm established in the previous work (Zhu et al.
    Nature Communications 2016), the active enhancer/promoter interaction center site in the genome was discovered, and this type of site is called hotspot .
    Targeted fragment deletion of non-coding hotspot enhancer sites by CRISPR/Cas9 system and high-throughput functional screening revealed a series of sites that are closely related to cell growth and survival .
    This study is the first to show that deletion of this class of enhancer sites can alter a wide range of chromatin structure, affecting cellular homeostasis through the synergistic effect of simultaneously affecting the expression of multiple non-essential genes .



    Due to the lack of high-resolution Hi-C data that can effectively discover enhancer/promoter interactions, this study used the EpiTensor algorithm with a resolution of up to 200-bp to predict 73 normal cell lines and 5 cancer cell lines Active enhancer/promoter three-dimensional interactions in /tissue obtained hotspots of strong interaction sites of enhancer-promoter, enhancer-enhancer, and promoter-promoter
    .
    Wei Wensheng's team found that the regulatory element interaction network (REIN) is a small-world network, that is, it is not affected by random destruction of nodes but is very sensitive to targeted destruction of high-value nodes (Figure 1A-B)

    .
    In order to explore whether hotspot sites are involved in stabilizing the three-dimensional structure of chromatin, the collaborative team used the CRISPR/Cas9 system-mediated pgRNA fragment deletion strategy established in the laboratory to perform high-level analysis on 751 selected non-coding hotspot enhancer sites in K562 cells.
    A flux functional screen identified 43 important functional regions (called essential hotspots) affecting cell survival or proliferation (Fig.
    1C)

    .
    Among them, deletion of the hotspot_10_25 (chr10: 74,123,469–74,1248,68) locus resulted in significant cell death or growth inhibition in K562 cells without affecting a variety of other cancer cells (Fig.
    1D)

    .

    Figure 1 Discovery and high-throughput functional screening of hotspot sites

    In order to explore whether the deletion of the hotspot site affects chromatin structure, the collaborative team selected the hotspot_10_25 site for further study, which does not interact with any essential genes
    .
    Hi-C analysis found that the effective diameter (effectivediameter) and modularity score (modularityscore) of the 6–8 Mb region in the vicinity of the site were significantly changed after deletion, and some regions that interacted with the region adjacent to the hotspot were observed (chr10 : 11–17 Mb) were also altered (Fig.
    2A–C)

    .
    Consistently, disruption of the topology-associated domain (TAD) was also found in the chr10: 12–14 Mb region

    .
    These changes in chromatin structure lead to changes in the interaction between enhancers and promoters of multiple genes, including CELF2, RSU1, FAM149B1 and CCAR1 (Fig.
    2D).
    These affected enhancers and promoters are not limited to deletion.
    Near the hotspot site, it can even be as far as 62 Mb

    .
    This suggests that deletion of hotspot loci can affect a wide range of chromatin structure, not limited to adjacent regions of its linear genome

    .
    Single-cell sequencing further found that the deletion of the hotspot site will activate the expression of a series of apoptosis-related genes, and can simultaneously affect the expression of multiple non-essential genes that interact with it in TAD.
    Studies have shown that the expression of multiple genes changes The synergistic effect could significantly affect cell survival (Fig.
    2E)

    .
    This study reveals for the first time the importance of noncoding regulatory element enhancers in stabilizing the three-dimensional structure of chromatin beyond the known regulation through direct interactions between enhancers and promoters

    .

    Figure 2.
    Deletion of hotspot loci results in large-scale 3D chromatin structure and simultaneous changes in expression of multiple genes.

    It is worth mentioning that in November 2021, two research groups, Wang Wei and Wei Wensheng, jointly reported for the first time in Science Advances that a non-coding site hub without any epigenetic signal can stabilize the three-dimensional structure of chromatin and maintain cell survival ( Ding et al.
    ,
    Science Advances 2021)
    .
    Through systematic mining, high-throughput screening and in-depth functional analysis of two types of non-coding sites, hub and hotspot, the functional elaboration of non-coding regions of the genome will be further enriched, and their important roles in maintaining three-dimensional genome structure will be gradually revealed.
    role

    .

    Dr.
    Liu Ying from Peking University, Dr.
    Ding Bo from the University of California, San Diego, Ph.
    D.
    student Zheng Lina, and Dr.
    Xu Ping from Peking University are the co-first authors of the paper, and Wei Wensheng and Wang Wei are the co-corresponding authors of the paper

    .
    The research project was supported by the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission’s Life Science Frontier Innovation and Cultivation Program, Beijing Future Genetic Diagnosis Advanced Innovation Center, Peking University-Tsinghua Life Science Joint Center, China Postdoctoral Science Foundation, California Institute of Regenerative Medicine ( CIRM) and support from the National Institutes of Health (NIH)

    .


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