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    Home > Active Ingredient News > Study of Nervous System > Research reveals the mechanisms of genomic regulation in the evolution of the human brain

    Research reveals the mechanisms of genomic regulation in the evolution of the human brain

    • Last Update: 2021-03-03
    • Source: Internet
    • Author: User
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    The human brain originated in the long evolutionary process of life, the most significant changes are the cognitive function of the brain, reflected in the significant expansion of brain capacity and the high degree of fineness of brain structure.
    in the course of human evolution, "what genetic changes have created the human brain" is a long-term scientific problem that the academic community has been trying to solve.
    the formation of all organs, including the brain, is achieved through the development process, and the unique pattern of brain development in humans stems from the functional mutations that accumulate in the genome during evolution.
    However, because there are millions of sequence differences between species, only a few of which have important functional effects, how to establish causal links between key sequence differences in the genome and changes in brain development regulation and analyze the molecular regulatory mechanisms is a challenging subject.
    Primates have been used as biological and medical research models for many years, macaques have close kinship with humans, and macaques are ideal animal models in the study of the origin, development mechanism and brain disease of the human brain.
    Mammals include the human genome, usually about 2 meters long, folded in a nucleus of only 10 microns, the genome in the three-dimensional space of the nucleus, such an orderly folding of the cell proliferation and orderly differentiation of the development process is of great significance.
    development of the latest high-volume histology techniques, such as hi-C, provides tools for fine analysis of the three-dimensional tissue and molecular regulation mechanisms of the genome during brain development.
    , the researchers conducted research on the 3D genome of cross-species brain development through cross-disciplinary collaboration.
    researchers used Hi-C technology to construct a high-resolution 3D genome map of the peak neurodevelopment of the brain of macaques in China, which is currently the highest resolution 3D genome map of primate brains, including humans, reaching a resolution of 1.5kb, which can accurately analyze the spatial tissue of the brain's developing genome.
    addition, the transcriptional map of the macaque fetal brain, the chromatin open area map and the distribution map of chromatin anchor protein CTCF were analyzed.
    Combining multi-group mapping data from these macaque fetal brains, the researchers for the first time constructed fine spatial images of chromatin in the development of the macaque fetal brain, identifying chromatin structures at different scales, including chromatin region chambers, chromatin topology domains (TADs) and chromatin rings (Loops), as well as regulatory elements (e.g. enhancers, initiations, etc.) that play an important role in brain development.
    by integrating with published public data, the researchers compared the 3D genomes across species (humans, macaques and mice) and found a larger number of human-specific chromatin structures, including 499 human-specific TADs and 1,266 human-specific Loops.
    these human-specific Loops remarkable rich-enhancing sub-interoperability regulation patterns, suggesting that brain development evolved more sophisticated transcriptional regulatory networks in human ancestors.
    researchers have integrated single-cell expression spectrum data analyzing human brain development and found that these human-specific Loops-regulated genes are significantly expressed at the SP layer of the fetal brain, leading to speculation that human-specific Loops may play an important role in human-specific development patterns at the SP layer. The SP layer of
    fetal brain is an important brain layer of early neuropathy and neuroplasticity formation in the early stage of brain development, in the course of human evolution, the SP layer has shown remarkable expansion, its thickness can reach about 4 times the thickness of the cortical layer, but because after the birth of the fetus, the brain layer gradually disappeared, the academic community has little understanding of its formation mechanism and function.
    this study provides evidence for the first time on the important role of the SP layer in the development and formation of human-specific brain structures.
    In addition, the study found that more human-specific mutations in the genome, including point mutations and structural mutations, are located in the TAD boundary zone and the Loop anchoring region, which may lead to the production of new transcription factor binding site in human brain development and the formation of human-specific chromatin advanced structures.
    For example, the SPHA7 gene, expressed specifically at the SP layer, is one of the key genes for the differentiation of nerve cells in brain development, and there are multiple human-specific sequence mutations upstream of the gene, which may lead to the emergence of human-specific enhancers and the formation of human-specific Loop.
    the enhancer knock-out experiment, the researchers confirmed that EPHA7's human-specific regulatory network interferes with its function and affects the process of nerve cell differentiation.
    For the first time, the study produced high-precision 3D genomics mapping resources for non-human primates, and using cross-species multi-histological analysis of the brain's 3D genome, it found human-specific chromatin structure and brain development control elements, which provided new ideas and evidences to clarify the evolutionary mechanisms of human brain development.
    research paper was published online in Cell.
    Luo Xin, Associate Researcher, Kunming Institute of Zoology, Chinese Academy of Sciences, Liu Yuxuan, Ph.D., Peking University, and Party Dachang, Ph.D. Candidate of the Institute of Mathematics and Systems Science of the Chinese Academy of Sciences, are co-authors of the paper.
    research has been supported by projects of the Chinese Academy of Sciences, the National Natural Science Foundation of China, the Ministry of Science and Technology and the relevant funds of Yunnan Province.
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