Nature Special Issue: A key step in cracking the human brain

The circuit of the human brain contains more than 100 billion neurons.

However, in recent years, revolutionary advances in imaging, sequencing, and computing technologies have opened up the possibility of truly mapping the human brain at the resolution of molecular and cellular components

In a special issue of Nature published online on October 7, 2021, researchers from the University of California, San Diego describe their progress

"In order to truly understand the function of the brain and develop new drugs and therapies from this knowledge to improve human life and health, we need to see and quantify the structure, organization and function of the brain down to the level of individual cells," University of California Said Dr.

Eran A.

Elements of gene regulation

Since 2006, the international community has been working together to create a three-dimensional map of the mouse brain

In the research paper, the scientists focused on creating a map of gene regulatory elements in the mouse brain, the youngest evolved areas in the brain that support advanced sensory perception, motor control, and cognitive functions

Recent investigations of mouse and human brains have shown that the brain contains hundreds of types of nerve cells distributed in different regions, but the transcriptional regulatory program-responsible for each cell's unique pattern of gene expression, so its identity and function-remains unknown

Professor Ren’s team investigated and analyzed chromatin, began analysis in more than 800,000 individual cell nuclei in adult mouse brains, and then used the data to map the states of 491,818 candidate gene DNA elements to different cell types

They found that different types of neurons are located in different areas of the mouse brain, their spatial distribution and functional specificity are interrelated, and they are likely to be driven by a unique set of cis-regulatory DNA elements within each cell type.

Surprisingly, most of the cis-regulatory elements in the mouse brain drawn by the researchers have homologous or similar sequences in the human genome.

Professor Ren said that these findings lay the foundation for a comprehensive analysis of the gene regulation program in the mammalian brain, including humans, and help explain the non-coding risk variants that lead to various neurological diseases and characteristics in humans

Transcriptome and epigenome elements

Each cell or group of cells produces a unique pattern of RNA transcripts-RNA strands transcribed from DNA to deliver genetic instructions to proteins that guide and sustain life

Mukamel and his colleagues focused advanced sequencing technology on the primary motor cortex of mice, which is a brain area that is essential for exercise

Using new computational and statistical models, they created a multimodal map of 56 neuronal cell types in the primary motor cortex of mice, fully describing their molecular, genomic and anatomical characteristics
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Mukamel said that this study shows that every brain cell has a coordinated pattern of gene expression and epigenetic regulation that can be identified with high fidelity using different sequencing technologies
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Just as a person has unique handwriting, facial features, voice patterns, and personality traits, the researchers found that the RNA and DNA characteristics of the cell types in the motor cortex distinguish each cell from its neighbors
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Mukamel said that just as our human personality contributes to the strength and diversity of our communities, the unique patterns of gene expression and regulation in brain circuits support a highly diverse network of cells with special roles and interdependent functions
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By combining epigenome and transcriptome data from an unprecedented number of cells, this study demonstrates the potential of single-cell sequencing technology to map brain cell types in a comprehensive way, which will help understand the more complex circuits in the human brain
.

references:

“ An atlas of gene regulatory elements in adult mouse cerebrum ” 
Co-authors include: Yang E.
Li, Sebastian Preissl, Xiaomeng Hou, Ziyang Zhang, Kai Zhang, Yunjiang Qiu, Olivier Poirion, Bin Li, Joshua Chiou, Naoki Kubo, Rongxin Fang, Xinxin Wang, Jee Yun Han, Yiming Yan, Michael Miller, Samantha Kuan, David Gorkin, Kyle J.
Gaulton and Eran A.
Mukamel, all at UC San Diego; Hanqing Liu, Jacinta Lucero, Antonio Pinto-Duarte, Michael Nunn and M.
Margarita Behrens, Salk Institute; Xiaoyu Yang and Yin Shen, UCSF; and Joseph R.
Ecker, Salk and Howard Hughes Medical Institute.

“ A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex ”
Co-authors include: Zizhen Yao, Darren Bertagnolli, Tamara Casper, Kirsten Crichton, Nick Dee, Olivia Fong, Jeff Goldy, Mike Hawrylycz, Matthew Kroll, Kanan Lathia, Delissa McMillen, Thuc Nghi Nguyen, Thanh Pham, Christine Rimorin, Kimberly Smith , Josef Sulc, Michael Tieu, Amy Torkelson, Herman Tung, Bosiljka Tasic, Hongkui Zeng and Cindy van Velthoven, all at Allen Institute for Brain Science; Hanqing Liu, Andrew I.
Aldridge, Anna Bartlett, Chongyuan Luo, Joseph R.
Nery, Sheng-Yong Niu, M.
Margarita Behrens, Jacinta D.
Lucero, Julia K.
Osteen, Antonio Pinto-Duarte, and Joseph R.
Ecker, all at Salk Institute; Fangming Xie, Wayne I.
Doyle, Rongxin Fang, Xiaomeng Hou, Olivier Poirion, Sebastian Preissl, Xinxin Wang and Bing Ren, all at UC San Diego; Seth A.
Ament, Jonathan Crabtree, Heather Creasy, Michelle Giglio, Victor Felix, Brian R.
Herb,Ronna Hertzano, Anup Mahurkar, Joshua Orvis, Héctor Corrada Bravo, Jayaram Kancherla, Owen R.
White, all at University of Maryland; Koen Van den Berge, Sandrine Dudoit, Elizabeth Purdom, Hector Roux de Bézieux and John Ngai, all at UC Berkeley ; Tommaso Biancalani, Elizabeth L.
Dougherty, Naeem M.
Nadaf, Eeshit Dhaval Vaishnav, Aviv Regev, Charles R.
Vanderburg and Evan Z.
Macosko, all at Broad Institute of MIT and Harvard; Yang Eric Li, Ludwig Institute for Cancer Research; Sina Booeshaghi, Valentine Svensson and Lior Pachter, all at California Institute of Technology; Carlo Colantuoni, Johns Hopkins University;; Qiwen Hu and Peter V.
Kharchenko, Harvard Medical School; Vasilis Ntranos, UCSF; Davide Risso, University of Padova; Angeline C .
Rivkin, Howard Hughes Medical Institute; Kelly Street, Dana-Farber Cancer Institute; Z.
Josh Huang,Stephan Fischer, Jesse Gillis, Megan Crow, Cold Spring Harbor; Joshua D.
Welch, University of Michigan.