New technology enables unprecedented glimpse inside single brain cells
Platform will provide open-source cell catalogue to better understand
brain diseases

Date:
March 9, 2022
Source:
Salk Institute
Summary:
Researchers have developed a new genomic technology to
simultaneously analyze the DNA, RNA and chromatin -- a combination
of DNA and protein - - from a single cell. The method, which took
five years to develop, is an important step forward for large
collaborations where multiple teams are working simultaneously to
classify thousands of new cell types. The new technology will help
streamline analyses.



FULL STORY ==========================================================================
Salk Institute researchers have developed a new genomic technology to simultaneously analyze the DNA, RNA and chromatin -- a combination of
DNA and protein -- from a single cell. The method, which took five years
to develop, is an important step forward for large collaborations where multiple teams are working simultaneously to classify thousands of new
cell types. The new technology, published in Cell Genomics on March 9,
2022, will help streamline analyses.


========================================================================== "This multimodal platform is going to be useful by providing a
comprehensive database that can be used by the groups trying to integrate
their single- modality data," says Joseph Ecker, director of the Genomic Analysis Laboratory at Salk, the Salk International Council Chair in
Genetics and Howard Hughes Medical Institute Investigator. "This new information can also inform and guide future cell-type classification."
Ecker believes this technology will be vital for large-scale efforts,
such as the National Institutes of Health's BRAIN Initiative Cell Census Network, which he co-chairs. A major effort of the BRAIN Initiative is to develop catalogues of mouse and human brain cell types. This information
can then be used to better understand how the brain grows and develops, as
well as the role different cell types play in neurodegenerative diseases,
such as Alzheimer's.

Current single-cell technology works by extracting either DNA, RNA
or chromatin from a cell's nucleus, and then analyzing its molecular
structure for patterns.

However, this method destroys the cell in the process, requiring
researchers to rely on computational algorithms to analyze more than
one of these components per cell or to compare the results.

For the new method, called snmCAT-seq, scientists used biomarkers to tag
DNA, RNA and chromatin without removing them from the cell. This allowed
the researchers to measure all three types of molecular information in
the same cell. The scientists then used this method to identify 63 cell
types in the frontal cortex region of the human brain and benchmarked the efficacy of computational methods for integrating multiple single-cell technologies. The team found the computational methods have high
accuracy in characterizing broadly defined brain-cell populations but
show significant ambiguity in analyzing finely defined cell types,
suggesting the necessity to define cell types by diverse measurements
for more accurate classification.

The technology could also be used to better understand how genes and
cells interact to cause neurodegenerative diseases.

"These diseases can broadly affect many cell types. But there could
be certain cell populations that are particularly vulnerable," says
co-first author Chongyuan Luo, assistant professor of human genetics
at the David Geffen School of Medicine at UCLA. "Genetic research has pinpointed the regions of the genome that are relevant for diseases
like Alzheimer's. We're providing another data dimension and identifying
the cell types affected by these genomic regions." As a next step, the
team plans to use the new platform to survey other areas of the brain,
and to compare cells from healthy human brains with those from brains
affected by Alzheimer's and other neurodegenerative diseases.

Other authors included Hanqing Liu, Bang-An Wang, Zhuzhu Zhang, Dong-Sung
Lee, Jingtian Zhou, Sheng-Yong Niu, Rosa Castanon, Anna Bartlett,
Angeline Rivkin, Jacinta Lucero, Joseph R. Nery, Jesse R. Dixon and
M. Margarita Behrens of Salk; Fangming Xie, Ethan J. Armand, Wayne
I. Doyle, Sebastian Preissl and Eran A. Mukamel of the University of
California San Diego; Kimberly Siletti, Lijuan Hu and Sten Linnarsson
of the Karolinska Institutet in Sweden; Trygve E.

Bakken, Rebecca D. Hodge and Ed Lein of the Allen Institute for Brain
Science in Seattle; Rongxin Fang, Xinxin Wang, and Bing Ren of the Ludwig Institute for Cancer Research in La Jolla, California; Tim Stuart and
Rahul Satija of the New York Genome Center; and David A. Davis and
Deborah C. Mash of the University of Miami.

The research was supported by the National Institutes of Health
(5R21HG009274, 5R21MH112161, 5U19MH11483, R01MH125252, U01HG012079, 5T32MH020002, R01HG010634 and U01MH114812), the Howard Hughes Medical
Institute and UC San Diego School of Medicine.


========================================================================== Story Source: Materials provided by Salk_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Chongyuan Luo, Hanqing Liu, Fangming Xie, Ethan J. Armand, Kimberly
Siletti, Trygve E. Bakken, Rongxin Fang, Wayne I. Doyle, Tim
Stuart, Rebecca D. Hodge, Lijuan Hu, Bang-An Wang, Zhuzhu Zhang,
Sebastian Preissl, Dong-Sung Lee, Jingtian Zhou, Sheng-Yong Niu,
Rosa Castanon, Anna Bartlett, Angeline Rivkin, Xinxin Wang,
Jacinta Lucero, Joseph R.

Nery, David A. Davis, Deborah C. Mash, Rahul Satija, Jesse R. Dixon,
Sten Linnarsson, Ed Lein, M. Margarita Behrens, Bing Ren, Eran
A. Mukamel, Joseph R. Ecker. Single nucleus multi-omics identifies
human cortical cell regulatory genome diversity. Cell Genomics,
2022; 2 (3): 100107 DOI: 10.1016/j.xgen.2022.100107 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220309131828.htm

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