Maintaining the unlimited potential of stem cells

December 4, 2018, Salk Institute
Jovylyn Gatchalian and Diana Hargreaves. Credit: Salk Institute

Embryonic stem cells (ESCs) are the very definition of being full of potential, given that they can become any type of cell in the body. Once they start down any particular path toward a type of tissue, they lose their unlimited potential. Scientists have been trying to understand why and how this happens in order to create regenerative therapies that can, for example, coax a person's own cells to replace damaged or diseased organs.

Scientists from the Salk Institute discovered a new complex that keeps the brakes on stem , allowing them to maintain their indefinite potential. The new complex, called GBAF and detailed in Nature Communications on December 3, 2018, could provide a future target for regenerative medicine.

"This project started as an exploration of embryonic stem cell pluripotency, which is this property that allows ESCs to become all different cell types in the body," says Diana Hargreaves, an assistant professor in Salk's Molecular and Cell Biology Laboratory and the senior author of the paper. "It's very important to know how various networks of genes control pluripotency, so finding a previously unknown protein complex that plays such an important regulatory role was very exciting."

Every cell in the body has the same set of DNA, which contains the instructions for making every possible cell type. Teams of large protein complexes (known as chromatin remodelers) activate or silence genes, directing an embryonic stem cell down a particular path. Like a team of contractors planning to renovate a house, these protein complexes contain varying subunits, the combination of which changes the physical shape of DNA and determines which genes can be accessed to direct the cell to become, for example, a lung cell or brain cell.

Hargreaves's team wanted to better understand how these subunits come together and how particular subunits might dictate a complex's function. So they turned to a protein called BRD9, which was known to associate with the BAF family of chromatin remodelers and was suspected to be a subunit. The team applied a chemical inhibitor of BRD9 to dishes of and performed a series of experiments to comprehensively analyze the cells' pluripotency in association with changes in BAF complex activity.

The group was surprised to discover that BRD9 acts as a brake on embryonic stem cell development. When BRD9 is working, cells retain their pluripotency, whereas when its activity is inhibited cells start moving on to the next stage of development. Further work to identify which BAF complexes were at work in the cells revealed another surprise: BRD9 was part of an as-yet-unknown BAF complex.

"For me, what was most exciting about our study was the fact that we had discovered a new BAF complex in embryonic ," says Jovylyn Gatchalian, a Salk research associate and the paper's first author.

Adds Hargreaves, "What we see with this work is that there's biochemical diversity at the level of individual variants of the BAF complex that allows for greater regulatory control. Understanding the complexities of that control is going to be key to any regenerative therapies."

Explore further: Scientists find new drug targets in aggressive cancers

More information: Jovylyn Gatchalian et al. A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells, Nature Communications (2018). DOI: 10.1038/s41467-018-07528-9

Related Stories

Scientists find new drug targets in aggressive cancers

November 5, 2018

Scientists have discovered a previously unknown molecular vulnerability in two rare, aggressive, and hard-to-treat types of cancer, and say it may be possible to attack this weakness with targeted drugs.

Controlling gene activity in human development

December 6, 2016

Researchers at the Babraham Institute have revealed a new understanding of the molecular switches that control gene activity in human embryonic stem cells. This insight provides new avenues for improving the efficiency of ...

Getting straight to the heart of the matter in stem cells

December 21, 2017

The process by which embryonic stem cells develop into heart cells is a complex process involving the precisely timed activation of several molecular pathways and at least 200 genes. Now, Salk Institute scientists have found ...

Genes that control embryonic stem cell fate identified

July 10, 2008

Scientists have identified about two dozen genes that control embryonic stem cell fate. The genes may either prod or restrain stem cells from drifting into a kind of limbo, they suspect. The limbo lies between the embryonic ...

Recommended for you

Strep bacteria compete for 'ownership' of human tissue

December 10, 2018

A well-accepted principle in the animal kingdom—from wasps to deer—is that creatures already occupying a habitat nearly always prevail over competitors from the same species that arrive later. Such infighting for the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.