If heterochromatin is to stay loose, it must be tightly regulated, report scientists based at The Babraham Institute. These scientists followed up on research indicating that in embryonic stem cells (ESCs), heterochromatin tends to stay “open”—not just open in terms of its organization, but open for business. Open heterochromatin, it is widely believed, keeps stem cells open to different developmental fates. Yet the Babraham scientists, along with collaborators in the U.K., Canada, and Japan, hoped to arrive at a deeper understanding. These scientists decided to investigate how epigenetic factors are connected to pluripotency.
The scientists focused on Nanog, a pluripotency factor, and found that it is part of a molecular pathway that controls heterochromatin organization in mouse ESCs. Unexpectedly, this pathway assigns new roles for several well-known stem cell factors.
Details of the scientists’ work appeared April 28 in the journal Genes & Development, in an article entitled, “The Pluripotency Factor Nanog Regulates Pericentromeric Heterochromatin Organization in Mouse Embryonic Stem Cells.” The article, which provides evidence for a connection between stem cell factors and the control of genome architecture, could lead to new ways to improve the quality and stability of ESCs, thereby enhancing the potential of stem cells in regenerative medicine.
The scientists found that deletion of Nanog leads to chromatin compaction and the remodeling of heterochromatin domains. The scientists also determined that forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin.
“NANOG associates with satellite repeats within heterochromatin domains, contributing to an architecture characterized by highly dispersed chromatin fibers, low levels of H3K9me3, and high major satellite transcription, and the strong transactivation domain of NANOG is required for this organization,” wrote the authors of the Genes & Development article. “The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG, and loss of Sall1 recapitulates the Nanog-null phenotype, but the loss of Sall1 can be circumvented through direct recruitment of the NANOG transactivation domain to major satellites.”
Essentially, the research showed that the stem cell factors Nanog and Sall1 bind to heterochromatin and help to maintain heterochromatin in an open form. ESCs lacking Nanog and Sall1 showed major defects in heterochromatin organization, including the closure and compaction of the chromatin. Loss of heterochromatin regulation has potential consequences for the long-term genetic stability of stem cells and the ability of stem cells to mature into specialized cell types.
“This unanticipated connection between stem cell factors and heterochromatin organization is important because it tells us about how stem cells work,” said Peter Rugg-Gunn, Ph.D., senior author on the research paper and research group leader at The Babraham Institute. “By tapping into this newly identified connection, we open up new avenues for more successful reprogramming of adult cells to a stem cell state, which is a priority for future regenerative medicine approaches.”