Here comes the 3000-plus brain cell genome HD map

high-definition 3D structure of key genes in brain cells. On the left are genes from the father and on the right are genes from the mother.
Mammals have different brains and different brain cells: about 100 billion brain nerve cells in humans, about 530 million in dogs, and about 70 million in mice. So what does a single brain cell look like? What is the connection between their shape and function?
January 22nd, a study published in Cells resulted in transcriptional group diagrams and 3D genome atlases of more than 3,000 mammalian brain cells. Based on these data, researchers can help with the diagnosis and treatment of neurodevelopmental and related diseases. The study was led by Xie Xiaoliang, director of the Center for Frontier Innovation in Biomedical Sciences at Peking University.human exploration of life is endless.
1953, the world's first DNA model was developed, and the double helix structure was deeply rooted in the hearts of the people. In 2001, a sketch of the human genome was published, and the human genetic code was deciphered to an unprecedented degree. Today, as genomics becomes a big sub-field of biology, scientists are increasingly understanding the phrase "structural determining function":
is not just a genome sequence, but the three-dimensional structure of the DNA molecule itself has important implications for the function of individual cells.
the genome structure of each cell is different. Thanks to ever-updated techniques, scientists have been able to build a three-dimensional structure of the mammalian single-celled genome, said Xie Xiaoliang, one of the authors of the 2018 study, published in Science.
the results were released thanks to a series of technologies, one of which, single-cell chromatin conformation capture, played a key role.
at the time, Tan Longzhi, a postdoctoral member of Xie Xiaoliang's team, was involved in the development of related technologies. The new results, published in Cell, are based on technologies such as Dip-C.
Past techniques have failed to measure the three-dimensional genome structure of single cells, and there has been no single-celled data on postpartal development of mammalian brains," tan Longzhi, lead author of the paper and a postdoctoral fellow in Stanford University's Department of Bioengineering, told China Science.of individual nerve cells in the cerebral cortical layer, with a resolution of 20kb. (Photo Source: Xie Xiaoliang Group) before joining Peking Universityfull-time, Xie Xiaoliang worked in single-molecule biology research at Harvard University in the United States for many years. In 2012, Xie Xiaoliang's team introduced a new method of single-cell genome-wide uniform amplification, multiple aeration cycle amplification (MALBAC), which greatly improved the range and accuracy of single-cell sequencing.
"MALBAC is a very unique and innovative single-cell sequencing technology," says Mr Tan, who says the technology is design-oriented and focuses on improving amplification erration ability to sensitively and accurately measure DNA and RNA in single cells.
this, the team has been working to develop high-precision single-cell sequencing methods. In 2017, Xie Xiaoliang and his colleagues Chen Chongyi, Yan Dong, Tan Longzhi, Li Heng and others used RNA instead of DNA copies to amplification the genome, and the linear amplification of the single-cell genome (linear amplification via transposon insertion, LIANTI) was introduced to further improve the veracity and accuracy of sequencing.
from an biological point of view, humans, a considerable number of higher animals are double. But for a long time after genomics was born, structural measurements of individual medocular cells were not possible. In 2018, the team developed Dip-C technology to expand the scope of research from thx to dip. The 46 chromosomes in humans were divided into two sets, and the 23 chromosomes in the set were derived from their parents, with sequence similarities as high as 99.9%, with very small differences, but with Dip-C technology, researchers were able to distinguish between the two sets of chromosomes.
To date, Dip-C remains the only way to measure the high-resolution 3D genome-wide structure of individual diplioma cells. Mr Tan said.
with the continuous refine of sequencing technology, related research findings are also more and more. For example, as the nuclei of a cell's "brain", the internal chromatin plays an important role in cell-specific gene expression - both vision and smell are closely related to highly specialized functional neurons, whose genomes have unique three-dimensional structures that are likely to determine their functions.
the newly published study, Xie Xiaoliang et al. used an upgraded version of MALBAC technology: MALBAC-DT (Digital Transcriptomics). After further improving sensitivity and accuracy, the team obtained for the first time a single-cell transcriptional map of the mammalian brain during postpartal development, with a specific number of 3,517. Using the Dip-C method, they completed 3,646 atlases of three-dimensional genome structures.
based on these data, they have made a lot of interesting discoveries. based on data from the transcriptional map, the team found that after the mice were born, a large number of genes were dynamically expressed, resulting in the formation of two gene expression modules in their innies and adults. "This suggests that there are significant differences in gene expression between the primary and adult brains and may affect the formation of cognitive function in the brain." Mr Tan said.
Combining a 3D genome atlas with a transcriptional group set, Tan and others found that within a month of birth, the brain changed at both the three-dimensional structure and the transcription group level, meaning that the brain did transform at the molecular level.
" occurs at a time when the brain begins to receive external sensory stimuli, the first month after the birth of a mouse. Tan longzhi said.
, are these molecular changes caused by external sensory stimuli?
to this problem, the team started with visual studies and kept the born mice in a dark environment to avoid visual stimulation. But they found that the three-dimensional genomes and transcription group transformations of the visual cortical layers of these "hiddenly bred" mice were almost unaffected by the aftergly edging, so the answer was no.
Another interesting finding is that in previous studies, Tan Longzhi and Xie Xiaoliang and others have found unique internal shifts in the genomes of olfactory cells: many of the gene regions that normally appear on the surface of the nucleus of the cells move significantly into the nucleus as the nerve cells differentiate. This phenomenon plays an important role in the regulation of olfactory receptors.
study, published today, the team found that this intra-shifting phenomenon is also present in various nerve cells in the brain, occurring about a month after the birth of mice. "This finding suggests that the central and peripheral neural cell lines may share some special pathps in the structure of the three-dimensional genome, which could be studied in depth in the future." Tan longzhi said.
, the team will expand the scope of application of existing technologies and continue to develop new methods of sequencing. Tan said they will further measure the three-dimensional genome structure, transcription group or other groups of individual cells, "biologically, we will measure more organs, more cells older, and more fully explain the molecular principles of mammalian development." The structure of a single sea mass nerve cell, with a resolution of 20kb. (Photo source: Xie Xiaoliang Task Force)
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