A study uncovers the 'grammar' behind human gene regulation
The logic that controls gene regulation in human cells

Date:
February 22, 2022
Source:
University of Helsinki
Summary:
A research group has discovered the logic that controls gene
regulation in human cells. In the future, this new knowledge
can be applied to, for example, investigating cancers and other
genetic diseases.



FULL STORY ==========================================================================
Gene regulation is an important process that controls the activity of
genes in cells.Incorrect gene regulation can contribute to the onset of
many diseases, including cancer.


==========================================================================
The DNA of the human genome contains genes that code for proteins, which
in turn give muscle cells their strength and brain cells their ability
to process information. DNA also contains gene regulatory elements that determine when and where genes are expressed -- so that muscle genes
are expressed in muscles and brain genes in the brain.

However, the regulatory code that determines gene activity remains poorly understood. Even though the human genome comprises almost three billion
base pairs, it is too short for learning the gene regulatory code from
the genomic sequence alone. The problem is similar to that faced by a
linguist who tries to understand a forgotten language on the basis of
a few short texts.

A research group of Professor Jussi Taipale that belongs to the Academy
of Finland's Centre of Excellence in Tumour Genetics Research, has now
found a way around this problem to solve the regulatory code.

The new study was recently published in the Nature Genetics journal.

"We measured the gene regulatory activity from a collection of DNA
sequences that together are 100 times larger than the entire human
genome," says Academy of Finland Research Fellow Biswajyoti Sahu, the
first author of the study.



========================================================================== "Instead of using the natural genomic sequence, we introduced random
synthetic DNA sequences to human cells. Then, the cells themselves
were allowed to read the new DNA and highlight for us the sequences
that function as active regulatory elements," Sahu adds, describing the innovative approach.

Researchers identify the key atomic unit of gene expression The
researchers produced their extensive dataset using a technique known
as massively parallel reporter assay, where the regulatory activity of
millions of DNA sequences can be simultaneously studied in one large-scale assay. The data were analysed using artificial intelligence tools.

Gene expression is regulated by proteins that bind the DNA, known as transcription factors. The researchers found that the very short DNA
sequences to which these factors bind constitute the key atomic unit of
gene expression.

Individual transcription factors contribute to gene regulation in an
additive manner. In other words, each factor increases regulatory activity independently without specific interactions with other factors. In
addition, transcription factors may have several parallel functions in
the gene regulatory process, such as enhancing the rate of gene expression
or defining the genomic location where the transcription starts.

"The binding motifs of transcription factors can be thought to be like
words that together define the cellular gene regulatory code," Professor
Jussi Taipale explains.



==========================================================================
The researchers found that the grammar for the code is relatively weak,
and that most words can be placed in almost any order without changing
their meaning.

"However, in some cases analogous to compound words, the grammar is
strong, and specific combinations of factors need to bind in a certain
order to activate gene expression," Taipale continues.

Only a handful of highly active transcription factors in cells The
researchers compared three different human cell types: colon and liver
cancer cells as well as normal cells originating from the retina. They
found that only a handful of transcription factors are highly active
in cells.

Furthermore, most transcription factor activities are similar regardless
of cell type.

The results revealed that the gene regulatory elements in the human
cells can be classified into different types based on the chromatin
context they are located in -- either in closed chromatin regions with
densely packed DNA, or in a more open chromatin environment where the
DNA is not as tightly packed around histone proteins.

Traditionally, active regulatory elements have been thought to be
located within open chromatin regions where DNA is easily accessible to transcription factors. Thus, the discovery of active regulatory elements
that function within closed chromatin regions is one of the central new observations of the study.

In addition, the researchers identified regulatory elements that are
dependent on chromatin. These elements are active at their normal sites
in the genome, but their activity drops considerably if they are removed
from their original location and transferred close to another gene.

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


========================================================================== Journal Reference:
1. Biswajyoti Sahu, Tuomo Hartonen, Pa"ivi Pihlajamaa, Bei Wei, Kashyap
Dave, Fangjie Zhu, Eevi Kaasinen, Katja Lidschreiber, Michael
Lidschreiber, Carsten O. Daub, Patrick Cramer, Teemu Kivioja,
Jussi Taipale. Sequence determinants of human gene regulatory
elements. Nature Genetics, 2022; DOI: 10.1038/s41588-021-01009-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220222135145.htm

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