A pluripotent stem cell may be imagined to be in a state of readiness—ready to differentiate into any of the cell types that exist in the body. But stem cells don’t pass through developmental stages only after differentiation begins. Stem cell pluripotency itself is fairly dynamic. For example, pluripotent stem cells pass through at least two distinct developmental stages: naïve embryonic stem cells and primed epiblast stem cells.

By examining the shifts in gene transcription that occur when stem cells progress from the embryonic to the epiblast stage, researchers at Case Western Reserve have identified a new class of genetic switch. The researchers included two groups of scientists with distinct skill sets. One group, led by Paul Tesar, Ph.D., specialized in stem cell biology. The other group, led by Peter Scacheri, Ph.D., specialized in genomics.

Using transcriptomic and epigenomic mapping, the researchers showed that a small fraction of transcripts are differentially expressed between mouse embryonic stem cells (mESCs) and primed mouse epiblast stem cells (mEpiSCs). The details of this work appeared June 5 in Cell Stem Cell, in an article entitled “Epigenomic Comparison Reveals Activation of ‘Seed’ Enhancers during Transition from Naive to Primed Pluripotency.”

“These genes show expected changes in chromatin at their promoters and enhancers,” wrote the authors. “Unexpectedly, the cis-regulatory circuitry of genes that are expressed at identical levels between these cell states also differs dramatically.”

In mESCs, these genes are associated with dominant proximal enhancers and dormant distal enhancers, which the authors term seed enhancers. In mEpiSCs, the naive-dominant enhancers are lost, and the seed enhancers take up primary transcriptional control.

Unlike most enhancers, which are only active in specific times or places in the body, seed enhancers play roles from before birth to adulthood. They are present, but dormant, in the early mouse embryonic stem cell population. In the more developed mouse epiblast stem cell population, they become the primary enhancers of their associated genes.

“Seed enhancers have increased sequence conservation and show preferential usage in downstream somatic tissues, often expanding into super enhancers,” the authors added.

“Our next step is to understand if misregulation of these seed enhancers might play a role in human diseases,” Dr. Tesar said. “The genes controlled by seed enhancers are powerful ones, and it’s possible that aberrations could contribute to things like heart disease or neurodegenerative disorders.”

“It is also clear that cancer can be driven by changes in enhancers,” Dr. Scacheri added. “We are interested in understanding the role of seed enhancers in cancer onset and progression.”

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