Cells manage which genes are active or inactive through gene regulation, a process fundamental for all cellular functions. Epigenetic regulation is one sophisticated method, involving changes in gene activity without altering the underlying DNA sequence. These changes often modify the proteins that package DNA.
Proteins frequently work in groups, forming complexes. The Polycomb Repressive Complex 2 (PRC2) is a multisubunit complex that modifies chromatin, the organized structure of DNA and proteins within the cell nucleus. PRC2’s primary role is to silence genes, ensuring they remain inactive when their products are not needed.
Core Components of PRC2
PRC2 is assembled from four core protein subunits, each contributing a specific function.
Enhancer of Zeste Homolog 2 (EZH2) serves as the catalytic subunit, responsible for the chemical modification that leads to gene silencing. An alternative, EZH1, can also serve a similar role in some PRC2 complexes.
Suppressor of Zeste 12 (SUZ12) functions as a scaffold, providing structural integrity. Its presence is necessary for EZH2 to maintain its stability and enzymatic activity. Embryonic Ectoderm Development (EED) acts as a reader, recognizing specific chemical marks that PRC2 itself creates. This recognition helps reinforce and maintain the silenced state of genes.
The final core components are Retinoblastoma-associated proteins RbAp46 and RbAp48 (RBBP7 and RBBP4). These proteins are histone chaperones, helping organize histone proteins, the spools around which DNA is wound. RbAp46/48 bind to histone H3-H4 heterodimers, assisting in PRC2 recruitment to specific locations on nucleosomes. They contribute to the proper establishment and maintenance of chromatin structure.
Gene Silencing Mechanism
PRC2 initiates gene silencing by being recruited to specific gene regions. This recruitment can occur through various mechanisms, including interactions with non-coding RNAs or CpG islands. Once positioned at a target gene, the enzymatic subunit, EZH2, performs a precise chemical modification.
EZH2 adds three methyl groups to lysine at position 27 on histone H3. This creates a distinctive mark known as trimethylated Histone H3 Lysine 27 (H3K27me3). This H3K27me3 mark functions as a molecular signal and binding site for other proteins, including those from the PRC1 complex, which further contributes to gene repression.
The addition of the H3K27me3 mark and subsequent protein binding leads to a physical change in chromatin structure. The DNA and its associated histone proteins become more tightly packed and condensed. This compaction makes the genetic material physically inaccessible to the cellular machinery responsible for reading and activating genes, effectively turning the gene off.
Function in Development and Cell Identity
The precise control exerted by PRC2 is fundamental for embryonic development. As a multicellular organism forms, unspecialized embryonic stem cells differentiate into specific cell types. PRC2 plays a central role by selectively silencing genes not required for a particular cell’s identity. For example, it ensures that genes specific to nerve cells remain inactive in a developing muscle cell, allowing proper specialization.
During early embryonic development, PRC2 activity is especially important. Loss of PRC2 function during this period can lead to embryonic lethality. Many developmental genes in embryonic stem cells exist in a “bivalent” state, marked by both the repressive H3K27me3 and an activating histone mark. This allows these genes to be poised for activation, but held in check by PRC2.
As cells commit to a specific lineage and differentiate, PRC2’s occupancy at these bivalent genes is often reduced, and the H3K27me3 mark is removed. This allows the appropriate developmental genes to become active. Beyond initial development, PRC2 helps maintain cell identity throughout an organism’s life. It ensures that a specialized cell, like a skin cell, keeps inappropriate genes silenced, preventing it from acquiring characteristics of another cell type. This mechanism of maintaining lineage fidelity is fundamental for tissue function and stability.
Implications in Disease
When PRC2 regulation goes awry, it can contribute to various diseases, with a significant link to cancer. Both excess PRC2 activity and reduced function can have harmful consequences.
Overactivity, or “gain-of-function,” of PRC2, often due to mutations in its EZH2 subunit, is observed in several cancer types. In cancers such as lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma, mutations can make EZH2 hyperactive. This leads to an exaggerated silencing of genes that would normally suppress tumor growth. Overexpression or amplification of EZH2 is also seen in various other cancers and is frequently associated with a less favorable prognosis.
Conversely, the inactivation or “loss-of-function” of PRC2 can also promote cancer. Mutations that disable PRC2 components are recurrent in malignant peripheral nerve sheath tumors (MPNSTs), where complete PRC2 inactivation occurs in a significant percentage of high-grade cases. In these tumors, the loss of PRC2’s silencing function allows genes that drive cell growth and metastasis to be inappropriately activated. PRC2 inactivation is also found in certain leukemias, such as T-cell acute lymphoblastic leukemia, and myelodysplastic syndromes. Beyond cancer, dysregulation of PRC2 has also been connected to various developmental disorders.