The study reveals the three-dimensional genomic regulation mechanism of human brain evolution

Researcher Yu Bing of the Kunming Institute of Zoology of the Chinese Academy of Sciences and Researcher Li Cheng of the School of Life Sciences of Peking University, in collaboration with Zhang Shihua, Research Fellow of the Institute of Mathematics and Systems Science of the Chinese Academy of Sciences, published the latest research results online in the international leading academic journal Cell under the title "3D Genome of macaque brain reveals evolutionary innovations"
the study built the primate's highest-resolution three-dimensional (3D) genome map to date, revealing the evolutionary mechanisms of 3D genome participation in human brain development through cross-species multi-group analysis and experimental validation.
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.
genetic changes that have shaped the human brain in the course of human evolution are important scientific problems that the international scientific community has long sought to solve.
all organs, including the brain, are formed through the development process.
unique pattern of brain development in humans stems from the cumulative functional mutations of the genome during evolution.
However, since there are millions of sequence differences between species, and only a few of them have important functional effects, how to establish causal links between key sequence differences in the genome and regulatory changes in brain development and analyze the molecular regulatory mechanisms in them is a challenging subject.
primates have been used as biological and medical research models for nearly a hundred years.
macaques have close kinship with humans, and are the ideal animal model in the study of the origin, developmental mechanisms and brain diseases of the human brain.
mammals, including humans, are usually about two meters long and folded into nuclei of cells that are only 10 microns long.
genome is folded in an orderly manner in the three-dimensional space of the nuclei of the cell.
such an orderly fold is essential for cell proliferation and orderly differentiation during development.
development of the latest high-volume histology techniques, such as whole genome chromatin spatial image capture (Hi-C), provides a powerful tool for finely analyzing the three-dimensional tissue and molecular regulatory mechanisms of the genome during brain development.
, the researchers conducted a cross-disciplinary collaboration to study the 3D genome of cross-species brain development.
used Hi-C technology to build a high-resolution 3D genome map of the peak neurodevelopment of chinese macaques.
This is the highest resolution 3D genome map of the primate brain, including humans, reaching 1.5kb resolution, which can analyze the spatial tissue of the brain's developing genome with high precision, as well as the transcriptional map of the macaque fetal brain, the chromatin open area map, and the distribution map of the chromatin anchor protein CTCF.
Combining the multi-group mapping data of these macaque fetal brains, the researchers for the first time constructed a fine spatial image of chromatin in the development of the macaque fetal brain, and identified chromatin configurations 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 of transsexuals (humans, macaques, and mice) and found a large 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 suggest that brain development has evolved more sophisticated transcriptional regulatory networks in human ancestors.
Importantly, by integrating and analyzing single-celled expression spectrum data for human brain development, these human-specific Loops-regulated genes were found to be significantly expressed at the SP (subplate) 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.
fetal brain SP layer is an important brain layer in the early neural circuit and neuroplastic formation of brain development, in the course of human evolution, the SP layer appeared significant expansion, its thickness can reach about four times the thickness of the cortical layer.
but after the birth of the fetus, the brain layer gradually disappears and little is understood about its formation mechanisms and functions.
the results provide 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 researchers found that many 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.
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