New studies have explored how bivalency prepares genes for expression during the process of cell differentiation, shedding light on a traditional concept in the regulation of developmental gene expression and revealing an important mechanism that has yet to be thoroughly examined experimentally. These discoveries enhance our comprehension of the complex cellular processes that govern development, how different cell types emerge from stem cells, and the establishment of cell identity. Understanding these mechanisms is crucial not only for grasping fundamental biological principles but also for advancing regenerative medicine strategies.
Scientists in the Voigt lab have deepened our knowledge of how developmental genes are kept in a state of readiness, allowing them to be expressed on cue when the appropriate signals are present.
Histone proteins play a vital role in the careful organization of DNA within the nucleus, and they also serve as the location for modifications, known as epigenetic marks, that determine whether a gene is silenced or activated. One specific type of this regulation involves the presence of both activating and repressive marks at certain sites, a phenomenon referred to as bivalency. The Voigt lab at the Babraham Institute has investigated how bivalency works to prepare genes for expression during cell differentiation. Their research reveals critical insights into the complex cellular mechanisms that influence development, how stem cells differentiate into specific cell types, and how individual cell identities are formed. Understanding these dynamics is not only essential for grasping foundational biology but also holds promise for the future of regenerative medicine.
The interplay of activating and repressive marks is believed to keep genes in a state of readiness within undifferentiated cells, primed for complete activation or total and irreversible silencing based on differentiation signals.
The current research has uncovered part of how this equilibrium is maintained and pinpointed the protein interactors that recognize the bivalent condition and affect gene expression.
Dr. Devisree Valsakumar, a postdoctoral researcher in the Voigt lab, noted: “Bivalent marks act as gatekeepers of a poised status, similar to the ‘Set’ command in ‘Ready, Set, Go!’. Our later findings indicate that this regulation, which keeps genes in a ‘ready to go’ condition, is crucial for the correct specialization of cell types as they differentiate from stem cells.”
A significant aspect of the team’s success was their ability to create specifically modified histones and nucleosomes, which are structures where DNA is wound around histone proteins. By meticulously recreating these DNA and histone protein complexes for tailored protein interaction assays, the researchers demonstrated that at bivalent sites, certain proteins were attracted to the repressive mark (H3K27me3) rather than the activating mark (H3K4me3).
Importantly, they found that the bivalent combination of both marks permits the attachment of unique proteins that are not drawn to either mark independently.
Among these proteins is the histone acetyltransferase complex KAT6B (MORF), which they identified as a novel reader of bivalent nucleosomes and a regulator of bivalent gene expression during the differentiation of embryonic stem cells (ESCs).
When KAT6B was removed from embryonic stem cells, those cells demonstrated a reduced ability to differentiate into neurons compared to unmodified control cells. The team concluded that this reduction was due to KAT6B’s role in properly managing the expression of bivalent genes, highlighting its importance in maintaining the poised state of these genes and facilitating their activation during ESC differentiation.
Dr. Philipp Voigt, a tenure-track group leader in the Institute’s Epigenetics research program, expressed: “Our study sheds light on an enduring concept in the regulation of developmental gene expression, unveiling an important mechanism that has previously been overlooked. It also introduces a new level of histone-based regulation, suggesting that bivalency possesses greater complexity than previously recognized. We are eager to explore what other regulatory layers exist and how they contribute to gene poising and control during development.”
“I would like to express my gratitude to everyone who contributed to this work, including colleagues from my lab at Babraham, the Bioinformatics team, and my prior lab in Edinburgh, along with the proteomics core at the University of Edinburgh.”
Key Takeaways:
- Researchers from the Voigt lab have broadened our understanding of how developmental genes remain ready for activation when they receive the appropriate signals.
- New regulatory layers have been uncovered with the identification of proteins interacting with epigenetic marks that prepare developmental genes for expression.
- The study provides insights into how bivalency — the presence of both activating and repressive marks at the same genomic site — readies developmental genes for activation.
- Notably, the team found specific proteins that only recognize the bivalent state. The absence of one such protein, KAT6B, prevents neuronal differentiation in embryonic stem cells.
- This research enhances our understanding of the mechanisms behind developmental gene expression, which is vital for strategies to maintain cellular health as we age and for developing regenerative technologies like cell and tissue regeneration and cellular reprogramming.
