【Nature】Heavy! Scientists have mapped multiple omics genes for human brain development

This article is the original of the translational medicine network, please indicate the source when reprinting

Author: Sophia

The human brain is probably the most complex organ in the entire life world and has long been the object of fascination for researchers
.
However, studying the brain, especially the genes and molecular switches that regulate and guide its development, is not an easy task
.

So far, scientists have begun to use animal models, mainly mice, but their findings cannot be directly transferred to humans
.
The brain structure of mice is different, lacking the wrinkled surface
typical of the human brain.
Cell culture has limited value in this field because cells tend to spread over large areas as they grow on a dish, which is not in line with the natural three-dimensional structure
of the brain.

In a new study just published in the journal Nature, researchers have studied thousands of individual cells
within brain organoids in great detail at various time points.
Their goal is to characterize cells with molecular genetic scholarship, in other words, to take the sum of all gene transcripts (transcriptomes) as a measure of gene expression, while taking the accessibility of the genome as a measure
of regulatory activity.
Then, try to represent this data as a kind of atlas, showing the molecular fingerprint
of each cell within the organoid.

a molecular fingerprint

 01 

The researchers took a new approach to studying the development of the human brain: the organoids that are being grown and used — millimeter-sized three-dimensional tissues that can grow from so-called pluripotent stem cells
.
As long as these stem cells receive the right stimulation, researchers can program them to become any type of cell present in the body, including neurons
.
When stem cells aggregate into a small globular tissue and are then stimulated appropriately, they can even self-organize, forming three-dimensional brain organoids
with complex tissue structures.

However, this process yields a huge data set: each cell in the organoid has 20,000 genes, and each organoid is made up
of thousands of cells.

"This leads to a huge matrix, and the only way we can solve it is with the help of the right programs and machine learning,"
explains Jonas Fleck.
To analyze all of this data and predict gene regulation mechanisms, the researchers developed their own program
.
We can use it to generate a complete network of interactions for each individual gene and predict what
will happen in real cells when that gene fails.
”

Identify gene switches

 02 

The goal of this study was to systematically identify gene switches that have a significant impact on neuronal development in different areas of brain organoids
.

With the help of the CRISPR-Cas9 system, the ETH researchers selectively turned off one gene in each cell, turning off about two dozen genes
simultaneously throughout the organoid.
This allows them to find out the role of their respective genes in the development of brain organoids
.

"This technique can be used to screen for genes
associated with disease.
In addition, we can study the effects of these genes on the development of different cells within the organoid," explains Sophie Jansen
.

Check for pattern formation in the forebrain

 03 

To test their theory, the researchers chose the GLI3 gene as an example
.
This gene is the blueprint for the transcription factor of the same name, a protein
that docks at certain sites in DNA to regulate another gene.
When GLI3 is turned off, cellular machines cannot read the gene and transcribe it into an RNA molecule
.

In mice, mutations in the GLI3 gene can lead to malformations of the central nervous system
.
Its role in human neuronal development has not been explored before, but mutations in this gene are known to cause diseases
such as Greig polydactylia syndrome and Pallister Hall syndrome.
This GLI3 gene allowed the researchers to validate their theoretical predictions and determine directly in cell culture how deletions of this gene affect further development of brain organoids
.

"We demonstrated for the first time that the GLI3 gene is involved in the formation
of human forebrain patterns.
This has only been found in rats before," Treutlein said
.

The model system reflects developmental biology

 04 

"What's exciting about this study is that it allows you to use whole genome data from so many individual cells to hypothesize what a single gene does," she explains
.
"In my opinion, it's also exciting that these systems of models made in Petri dishes do reflect the developmental biology
we know from mice.
"

Treutlein also found how the medium produces self-organizing tissue with structures comparable to the structure of the human brain — not only at the morphological level, but also (as the researchers showed in their latest study) in gene regulation and pattern formation
.
Organoids like this are indeed a great way
to study the biology of human development.

Multifunctional brain organoids

 05 

The study of organoids composed of human cellular material has the advantage
of transferring the results to humans.
They can be used not only to study basic developmental biology, but also to study the role
of genes in diseases or developmental brain diseases.
Organoids can also be used to test drugs and may be used to culture transplantable organs or parts of
organs.

However, growing organoids takes time and effort
.
In addition, each cell clump develops individually, rather than in a
standardized way.
As a result, Treutlein and her team are working to improve organoids and automate
their manufacturing process.

Resources:

https://medicalxpress.
com/news/2022-10-human-brain.
html

c

Note: This article is intended to introduce medical research advances and cannot be used as a reference for
treatment options.
For health guidance, please visit a regular hospital
.

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