Gene regulation is a system that determines which genes are activated and which are silenced within a cell. This control is fundamental, allowing cells to develop into specialized types, such as muscle or nerve cells, despite all containing the same genetic blueprint. This process ensures that genes are expressed only at the correct time and place.
A group of proteins known as Polycomb Repressive Complex 1 (PRC1) is a part of this regulatory machinery. By modifying the structure of chromatin—the tightly packaged complex of DNA and proteins within the nucleus—PRC1 helps to keep specific genes in a long-term “off” state, which is vital for development.
Defining Polycomb Repressive Complex 1
Polycomb Repressive Complex 1 is a large, multi-protein assembly that maintains genes in a silent, or repressed, state. It does not initiate gene silencing but instead perpetuates a pre-existing repressive signal, locking in a cell’s fate. The discovery of this regulatory system dates back to studies in the fruit fly, Drosophila melanogaster, where Polycomb group (PcG) proteins were first identified.
This function is highly conserved across evolution, from insects to humans. PRC1 acts as a form of cellular memory, ensuring that once a gene is switched off during development, it remains off in that cell and all its descendants through subsequent cell divisions.
Core Components and Variations of PRC1
The PRC1 machinery is a family of related complexes with diverse compositions, allowing it to perform a wide range of regulatory functions in different cell types and developmental stages. The core of any PRC1 complex is a heterodimer formed by a RING1 protein (RING1A or RING1B) and a PCGF protein. The specific PCGF protein present—one of six different types in mammals—defines the PRC1 subcomplex. This leads to a distinction between canonical PRC1 (cPRC1) and variant PRC1 (vPRC1) complexes.
Canonical PRC1 complexes are built around PCGF2 or PCGF4 and include a Chromobox (CBX) protein. These CBX proteins contain a domain that allows them to recognize and bind to a histone modification called H3K27me3, a mark deposited by another Polycomb complex, PRC2. This interaction physically links the activities of PRC1 and PRC2.
Variant PRC1 complexes are more diverse and lack CBX proteins. Instead, they contain proteins like RYBP or YAF2, which do not bind the H3K27me3 mark but enhance the catalytic activity of the RING1A/B ligase. Other components include Polyhomeotic (PHC) proteins, found in canonical versions, which contribute to chromatin compaction. The specific combination of these subunits results in distinct PRC1 assemblies with specialized roles.
How PRC1 Silences Genes
The primary mechanism PRC1 uses to silence genes is the enzymatic activity of its RING1A or RING1B subunit. These proteins are E3 ubiquitin ligases, meaning they attach a small protein tag called ubiquitin to other proteins. The target of PRC1 is the histone protein H2A, which DNA wraps around to form chromatin. PRC1 adds a single ubiquitin molecule to a specific location on H2A, creating a mark known as H2A monoubiquitination (H2AK119ub1).
This H2AK119ub1 modification is a repressive signal. The ubiquitin tag physically obstructs the transcriptional machinery and is thought to inhibit RNA polymerase II, the enzyme that transcribes DNA. This modification also promotes chromatin compaction, folding it into a dense structure inaccessible to activating proteins.
Recruitment of PRC1 to its target genes occurs through different pathways. Canonical PRC1 is often recruited to sites pre-marked by PRC2, with its CBX subunit binding to the H3K27me3 mark from PRC2. This creates a hierarchical system where PRC2 marks a gene for silencing and PRC1 reinforces that state. Variant PRC1 complexes can be recruited independently of PRC2, sometimes through interactions with specific DNA-binding transcription factors or by recognizing other chromatin features.
PRC1’s Functions in Biological Processes
The gene-silencing activity of PRC1 is involved in many biological processes, particularly cell identity and development. During embryonic development, PRC1 represses developmental regulator genes, such as the Hox genes, ensuring they are expressed only in the correct cells and at the proper time to establish the body plan. This control allows a single fertilized egg to give rise to all the diverse tissues of an organism.
In embryonic stem cells (ESCs), PRC1 is important for maintaining pluripotency—the ability of these cells to differentiate into any cell type. It achieves this by silencing the genes that would otherwise drive differentiation. As development proceeds, the targeted removal of PRC1 from specific genes allows for their activation, guiding the ESCs toward a specific cell fate.
This role extends into adult stem cell populations, where PRC1 helps maintain tissue homeostasis by regulating the balance between self-renewal and differentiation. It also contributes to other large-scale processes, such as X-chromosome inactivation in female mammals, where one X chromosome is silenced to ensure proper gene dosage.
When PRC1 Goes Awry: Implications for Disease
Dysregulation of PRC1 is linked to a variety of human diseases, most notably cancer and developmental disorders. When PRC1 function is compromised—through mutations, altered expression levels, or incorrect targeting—it can lead to the aberrant silencing or activation of genes, disrupting normal cellular processes.
In many types of cancer, including leukemias, lymphomas, and various solid tumors, components of the PRC1 complex are misregulated. For instance, the overexpression of certain PRC1 subunits can lead to the inappropriate silencing of tumor suppressor genes. These genes normally function to control cell growth, and their repression by PRC1 can lead to uncontrolled cell proliferation and tumor formation. Because of this, several PRC1 components are being investigated as potential therapeutic targets.
Mutations in the genes that encode PRC1 subunits can also cause severe developmental disorders. These genetic lesions disrupt the gene expression programs required for normal development, leading to congenital syndromes often characterized by intellectual disability, growth abnormalities, and other developmental defects.