The DREAM Complex in Cell Cycle and Transcriptional Regulation

Cells must regulate gene expression and cell cycle progression to maintain function and prevent diseases like cancer. The DREAM complex is a key regulator that controls transcription of genes involved in proliferation, quiescence, and differentiation.

Understanding how this complex functions offers insight into fundamental cellular mechanisms and potential therapeutic targets for diseases linked to dysregulated growth.

Composition And Architecture

The DREAM complex is a multi-protein assembly that controls gene expression across different cell cycle phases. It consists of the MuvB core—composed of LIN9, LIN37, LIN52, LIN54, and RBBP4—which provides structural support and interacts with transcriptional repressors like Retinoblastoma-like (RBL) proteins and E2F transcription factors. These components work together to regulate genes involved in the transition between quiescence and proliferation.

In quiescent cells, the complex associates with E2F4 or E2F5 and RBL1 (p107) or RBL2 (p130) to form a repressive configuration that silences genes necessary for cell cycle entry. This repression is reinforced by histone-modifying enzymes that create a chromatin environment less accessible to transcriptional machinery. When cells prepare to divide, the MuvB core dissociates from repressors and binds to B-MYB, activating genes needed for S-phase and mitosis.

Structural studies highlight LIN54’s role in DNA binding, recognizing promoter sequences that dictate DREAM’s target specificity. LIN52 stabilizes interactions with RBL proteins, ensuring proper repressive complex assembly in non-dividing cells. RBBP4, a histone-binding protein, suggests that the DREAM complex influences chromatin structure in addition to transcription factor interactions. These architectural features enable DREAM to respond dynamically to cellular cues, switching between gene silencing and activation.

Mechanisms In Cell Cycle Control

The DREAM complex regulates cell cycle transitions, particularly between G0 and G1, enforcing a repressive state that prevents premature division. In quiescent cells, it silences genes encoding cyclins, DNA replication factors, and mitotic regulators by recruiting chromatin-modifying enzymes that establish a repressive epigenetic landscape. This control is essential for tissues like neurons and muscles, where unregulated proliferation leads to dysfunction.

Upon receiving proliferative signals, DREAM undergoes structural changes that release its repressive components. Cyclin-dependent kinases (CDK4 and CDK6) phosphorylate RBL2 (p130), causing its dissociation from MuvB. This destabilizes the complex’s repression, allowing transcriptional activators to take over. The ubiquitin-proteasome pathway further degrades p130, ensuring the shift from quiescence to proliferation. Studies show that disrupting this phosphorylation prolongs quiescence and impairs proliferation.

Beyond G1/S control, DREAM ensures proper mitotic progression. In late G2, the MuvB core associates with B-MYB, forming an activation complex that drives expression of mitotic regulators like cyclin B1, PLK1, and aurora kinases. Disruptions in this phase lead to chromosome missegregation and aneuploidy, hallmarks of many cancers. Knockout models demonstrate that losing DREAM components results in defective mitotic entry and genomic instability, highlighting its role in orderly cell cycle progression.

Role In Transcriptional Regulation

The DREAM complex dynamically shifts between transcriptional repression and activation, aligning gene expression with cellular needs. Its function depends on associated cofactors that determine whether target genes remain silent or become active. In resting cells, DREAM recruits chromatin-modifying enzymes to maintain a transcriptionally inactive state, particularly in genes controlling the cell cycle.

The DNA-binding properties of LIN54 dictate target specificity by recognizing CHR (cell cycle homology region) promoter elements, which are enriched in mitotic genes. When DREAM associates with E2F4 and RBL2, these genes remain silenced. The transition to activation occurs when MuvB shifts to B-MYB, recruiting transcriptional coactivators that promote RNA polymerase II engagement. This precise timing prevents errors in chromosome segregation and division.

Epigenetic Interactions

DREAM influences chromatin structure by recruiting histone-modifying enzymes that regulate gene accessibility. Histone deacetylases (HDAC1 and HDAC2) remove acetyl groups, condensing chromatin and restricting transcription. This modification is prevalent in proliferation-controlling genes, preventing inappropriate cell cycle entry.

Beyond deacetylation, DREAM is involved in histone methylation, which can activate or repress transcription depending on the specific mark. The recruitment of polycomb repressive complexes (PRCs), which deposit H3K27me3 marks, reinforces gene silencing in non-dividing cells. When transitioning to activation, DREAM facilitates the removal of these marks and promotes histone acetylation, creating a permissive chromatin state. This dynamic interplay enables rapid switching between repression and activation in response to cellular cues.

Links To Cell Fate Decisions

DREAM plays a key role in determining whether a cell remains quiescent, re-enters the cycle, or differentiates. By regulating genes associated with proliferation and dormancy, it integrates external signals with intrinsic regulatory mechanisms. This function is especially important in stem cells, where balancing self-renewal and differentiation maintains tissue homeostasis.

In embryonic stem cells, DREAM represses proliferation-associated genes to prevent premature differentiation, ensuring commitment occurs only in response to developmental cues. In adult stem cells, it maintains quiescence, preserving long-term regenerative capacity and preventing exhaustion or senescence.

Dysregulation of DREAM is implicated in cancer, where loss of controlled cell fate decisions leads to unchecked proliferation. Mutations or altered expression of DREAM components disrupt the balance between quiescence and activation, promoting excessive division. Reduced RBL2 (p130) expression weakens DREAM-mediated repression, allowing uncontrolled gene activation. This not only drives proliferation but also impairs differentiation, contributing to highly proliferative, undifferentiated tumor cells. Targeting DREAM or its regulatory interactions is being explored as a therapeutic strategy to restore transcriptional control and curb tumor growth.