Genome Screening Technique may Repair Stem Cells

Genetic networks that drive the behavior of human embryonic stem cells have been found. This enables the genome-wide screening technique to reveal the mechanisms that may help remove damaged stem cells before they can compromise human development as per a study at the Brigham And Women's Hospital. Highly specialized human tissues are eventually differentiated under the light of a small collection of cells known as human embryonic stem cells (hESCs). hESCs are of central interest to developmental and regenerative biologists as similar to pluripotent cells.

hESC functioning is driven by many genes but the interrelated activities of these genes have only emerged more recently.

Study in Genes

A study at Brigham and Women’s Hospital and Harvard Medical School utilized genome-wide genetic screening to both over-express and inactivate (“knock out”) tens of thousands of genes in hESCs, as published in Genes and Development.

The key networks that simultaneously control pluripotency and readiness for cell death (apoptosis) were finally uncovered by the study. These findings offer new insights into cancer genetics and a novel approach for regenerative medicine research.

“Our methods allowed us to create an ‘atlas’ of nearly every gene in the human genome and determine what its over-expression or loss does to the most fundamental first steps of human development. Instead of looking at genes one by one, we looked at thousands of genetic alterations at the same time to determine how they affect the proliferation of embryonic stem cells, and, subsequently, the development of the three germ layers that serve as the raw material for human tissues,” says lead author Kamila Naxerova, Ph.D., a former postdoctoral fellow in the Elledge lab in the Brigham’s Division of Genetics.

The team knocked out roughly 18,000 genes and overexpressed 12,000 genes to find that hESC genes that control pluripotency, or differentiation capacities, play a unique role. On deleting these specific genes among them – OCT4 and SOX2, it was found that the stem cells surprisingly increased their resistance to death.

hESC activities and Genes

This indicates that under normal circumstances pluripotency regulators also contribute to apoptosis pathways.

It was thus hypothesized that the genetic link between pluripotency and tightly regimented cell death helps ensure that if a stem cell is damaged, it is destroyed early on in embryonic development before it can compromise the functioning of future cells and tissues.

These were evident in a pluripotency regulator known as the SAGA complex. In the absence of the SAGA complex, hESCs died less readily, testifying to the SAGA complex’s central role in a range of hESC activities.

“Genetic screens present a wonderful opportunity to probe how genetic networks contribute to interrelated cellular behaviors like growth, differentiation, and survival. This approach can help regenerative and developmental biologists systematically map out genetic networks that are involved in the formation of particular tissues and manipulate those genes to more efficiently grow different kinds of human tissues from stem cells,” says Naxerova who is now an assistant professor in the Center for Systems Biology at Massachusetts General Hospital.

Source-Medindia