Mapping cellular diversity by looking for common topics of gene control

April 09, 2019

A Belgian team of computational biologists led by Stein Aerts (VIB-KU Leuven) has developed a new bioinformatics method called cisTopic. Inspired by text-mining methods, cisTopic helps scientists to gain insight into the mechanisms underlying the differences in gene regulation across and within the cells in our body by looking for common topics. In a new publication in Nature Methods, Aerts and his team demonstrate the broad range of applications of this method, from brain research to cancer biology.

Our genomes are controlled by combinations of regulatory molecules that "switch on" target genes in our DNA. These regulatory molecules bind to so-called enhancer and promoter regions in our chromosomes. Understanding when and how they are activated, can teach us a lot about the cellular diversity in our bodies.

"All the cells in our body essentially contain the same DNA," explains prof. Stein Aerts, who heads the lab for computational biology at VIB and KU Leuven. "What makes every cell type unique is which genes are active at any given time."

Recent advances in single-cell technology have enabled scientists like Aerts to look at gene activity and the accessibility of regulatory DNA regions for thousands of individual cells. But this information has not yet solved the challenge of reverse engineering the genomic regulatory code.

Clustering cells

Carmen Bravo González-Blas and Liesbeth Minnoye, two young researchers in Aerts' lab, set out to tackle this problem. "The data we can obtain from a single cell, regarding accessibility of specific regulatory regions in its DNA, is very sparse. Yet, we wanted to group individual cells into clusters based on similarities of these accessible regions."

To tackle this problem, Bravo González-Blas borrowed a computational technique from the text-mining field, called "topic modelling". She explains: "In text mining, computers can discover "topics" from large collections of text, as well as terms that are important for each topic. When applied to our problem of gene control, the computer discovers topics that are important for each cell type in our body. It also allowed us to identify regulatory regions for each topic."

"We evaluated our new method on a variety of data sets, and found that it allows us to accurately recover both expected and new cell types," adds Minnoye. "Particularly on very sparse data, our method is more robust than previously developed approaches."

Learning more about complex tissues

The researchers applied cisTopic to cell populations that are biologically complex, such as the cells present in the mammalian brain. Not only did cisTopic allow them to recover the major cell types in the brain, but the team was also able to identify new subpopulations and master regulators of neuronal cell types.

"In addition to the brain, we also used cisTopic to investigate dynamic changes in gene accessibility in melanoma cell cultures from patients," adds Aerts. "When we modulated one of the known important modulators in these cancer cells, we could for the first time track changes in the accessibility of different DNA regions over time. Such approaches will finally allow us to better understand what these master regulators actually do in cancer cells, and which genes they control."

These different applications illustrate the value of the team's new method for studying the players and mechanism that orchestrate gene regulation in our cells. According to computational biologists like Aerts, this is an important step towards real-time and personalized monitoring of cell states in health and disease.
-end-
Publication

cisTopic: cis-Regulatory topic modelling on single-cell ATAC-seq data, Bravo González-Blas, Minnoye et al. Nature Methods

Questions from patients

A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: patienteninfo@vib.be?. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

VIB (the Flanders Institute for Biotechnology)

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.