Key networks controlling pluripotency and apoptosis during development revealed

During the early stages of human embryonic development, a small collection of cells called human embryonic stem cells (hESCs) co-ordinates growth and differentiation finally giving rise to highly specialized human tissues. hESCs are pluripotent cells—ascendants of each cell type in the human body—and are of great interest to developmental and regenerative biologists.

Embryonic Stem Cells

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Numerous genes regulating hESC functioning have been identified earlier. However robust tools that elaborate the interrelated activities of these genes have surfaced only recently. Scientists from Brigham and Women’s Hospital and Harvard Medical School utilized genome-wide genetic screening to over-express and inactivate (“knock out”) tens of thousands of genes in hESCs.

They revealed major networks that concurrently regulate pluripotency and apoptosis (readiness for cell death) aiding to assure optimal conditions for embryonic development. The observations provide a novel understanding of cancer genetics and a new approach for regenerative medicine research. The study was published in the Genes & Development journal.

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.”

Kamila Naxerova PhD, Study Lead Author, Brigham and Women’s Hospital

Naxerova is a former postdoctoral fellow in the Elledge laboratory in Brigham’s Division of Genetics.  

Naxerova further adds, “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.”

Elucidating how human embryonic stem cell function is controlled by genetics is essential for our understanding of developmental biology and regenerative medicine. Our study provides the most extensive examination of gene functionality in hESCs to date.”

Stephen Elledge PhD, Study Co-Corresponding Author and Gregor Mendel Professor, Genetics and Medicine, Brigham and Women’s Hospital

Elledge is also a professor at the Harvard Medical School.

While carrying out the analysis— overexpressing 12,000 genes and knocking out around 18,000 genes—the scientists identified an unusual role performed by hESC genes that regulate pluripotency, or differentiation capacities.  The scientists later deleted the well-known genes OCT4 and SOX2.

They found that the stem cells increased their resistance to death, signifying that under normal conditions, regulators also contribute to apoptosis pathways. The scientists assumed that the genetic association between pluripotency and closely regimented cell death assures that if a stem cell is damaged, it is annihilated early on in embryonic development before compromising the functioning of future cells and tissues.

These interrelated behaviors are particularly seen in a pluripotency regulator called the SAGA complex. The scientists for the first time showed that hESCs were destroyed less readily in the absence of the SAGA complex. Also, the absence of the SAGA complex inhibited the progress of all three germ layers (endoderm, mesoderm, and ectoderm), evidencing the major role of the SAGA complex in a range of hESC activities.

The scientists also found that most of the genes that control the formation of the three germ layers are contributors to cancer growth when they are under-or over-expressed in somatic cells.

Apart from providing a different outlook on the genetic basis of cancers, the research’s highly efficient genetic screening approach might enlighten future researches in regenerative biology.

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.”

Kamila Naxerova PhD, Study Lead Author, Brigham and Women’s Hospital

Naxerova is now an assistant professor in the Center for Systems Biology at Massachusetts General Hospital.

Source:
Journal reference:

Naxerova, K., et al. (2021) Integrated loss- and gain-of-function screens define a core network governing human embryonic stem cell behavior. Genes & Development. doi.org/ 10.1101/gad.349048.121.

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