Affinage

MED4

Mediator of RNA polymerase II transcription subunit 4 · UniProt Q9NPJ6

Length
270 aa
Mass
29.7 kDa
Annotated
2026-06-10
14 papers in source corpus 2 papers cited in narrative 2 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MED4 is a subunit of the Mediator transcriptional coactivator complex that functions in chromatin architecture and enhancer regulation (PMID:38014033). In retinoblastoma, MED4 is a survival gene: RB1-deficient cells cannot survive its loss in vitro or in orthotopic xenografts, defining a synthetic lethal interaction between RB1 loss and MED4 loss (PMID:24858910). Contrary to the canonical Mediator role in activating transcription, MED4 maintains 3D chromatin compaction and suppresses enhancer priming by preventing H3K4me1 deposition; its haploinsufficiency disrupts enhancer poise and reprograms enhancer dynamics to drive ECM gene expression and integrin-mediated mechanotransduction, enabling metastatic growth (PMID:38014033). Beyond these two contexts, no further mechanistic detail of MED4 has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2014 Medium

    Established that MED4 is selectively required for survival of RB1-deficient cancer cells, identifying a genetic dependency exploitable in retinoblastoma rather than a generic essential role.

    Evidence MED4 knockdown/loss in RB1-/- retinoblastoma cells assayed by in vitro viability and orthotopic xenograft models

    PMID:24858910

    Open questions at the time
    • Molecular mechanism linking RB1 loss to MED4 dependence not defined
    • Whether the synthetic lethality extends beyond retinoblastoma untested
    • No biochemical characterization of MED4's role within Mediator in this context
  2. 2024 Medium

    Reframed MED4 as a repressive chromatin regulator that maintains 3D compaction and enhancer poise, showing that its haploinsufficiency reprograms enhancers to drive ECM expression, mechanotransduction, and metastatic growth.

    Evidence Genome-scale genetic screen, syngeneic xenografts, chromatin conformation assays, H3K4me1 profiling, and enhancer/gene expression analysis (preprint)

    PMID:38014033

    Open questions at the time
    • Preprint, not yet peer-reviewed and from a single lab
    • Mechanism by which MED4 suppresses H3K4me1 deposition not resolved
    • Direct link between MED4 chromatin function and the RB1 synthetic lethality not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MED4's role within the Mediator complex mechanistically connects chromatin compaction, enhancer suppression, and RB1-dependent survival remains unresolved.
  • No structural or biochemical model of MED4 within Mediator in the corpus
  • No direct MED4 physical partners or substrates identified
  • Whether enhancer regulation and RB1 synthetic lethality share a common mechanism is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-4839726 Chromatin organization 1 R-HSA-74160 Gene expression (Transcription) 1
Complex memberships
Mediator complex

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 MED4 (Mediator subunit) is a survival gene in retinoblastoma: RB1-/- retinoblastoma cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, establishing a synthetic lethal relationship between RB1 loss and MED4 loss. In vitro cell viability assays and orthotopic xenograft models with MED4 knockdown/loss in RB1-/- retinoblastoma cells Human molecular genetics Medium 24858910
2024 MED4 maintains 3D chromatin compaction and enhancer landscape by preventing enhancer priming or activation through suppression of H3K4me1 deposition; contrary to the canonical Mediator role in activating gene expression. MED4 haploinsufficiency disrupts enhancer poise and reprograms enhancer dynamics to facilitate ECM gene expression and integrin-mediated mechanotransduction, driving metastatic growth. Genome-scale genetic screen, syngeneic xenograft models, chromatin conformation assays, histone modification profiling (H3K4me1), enhancer landscape analysis, gene expression profiling bioRxivpreprint Medium 38014033

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 A novel type of lycopene epsilon-cyclase in the marine cyanobacterium Prochlorococcus marinus MED4. Archives of microbiology 69 12712234
2012 Sequence analysis of a complete 1.66 Mb Prochlorococcus marinus MED4 genome cloned in yeast. Nucleic acids research 46 22941652
2003 Experimental and computational analysis of transcriptional start sites in the cyanobacterium Prochlorococcus MED4. Nucleic acids research 37 12771216
2005 A green light-absorbing phycoerythrin is present in the high-light-adapted marine cyanobacterium Prochlorococcus sp. MED4. Environmental microbiology 31 16156734
2004 Effects of high light on transcripts of stress-associated genes for the cyanobacteria Synechocystis sp. PCC 6803 and Prochlorococcus MED4 and MIT9313. Microbiology (Reading, England) 31 15133090
2003 Two-component systems in Prochlorococcus MED4: genomic analysis and differential expression under stress. FEMS microbiology letters 29 13129619
2014 The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion. Human molecular genetics 27 24858910
2014 The minimal CO2-concentrating mechanism of Prochlorococcus spp. MED4 is effective and efficient. Plant physiology 27 25315602
2013 Effects of phosphorus starvation versus limitation on the marine cyanobacterium Prochlorococcus MED4 I: uptake physiology. Environmental microbiology 24 23387819
2010 UV hyper-resistance in Prochlorococcus MED4 results from a single base pair deletion just upstream of an operon encoding nudix hydrolase and photolyase. Environmental microbiology 22 20345942
2019 Interplay and Targetome of the Two Conserved Cyanobacterial sRNAs Yfr1 and Yfr2 in Prochlorococcus MED4. Scientific reports 9 31586076
2014 The transcriptome landscape of Prochlorococcus MED4 and the factors for stabilizing the core genome. BMC microbiology 3 24438106
2025 Characterization of extracellular vesicles released from Prochlorococcus MED4 at the steady state and under a light-dark cycle. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 2 39842488
2024 Mediator Subunit Med4 Enforces Metastatic Dormancy in Breast Cancer. bioRxiv : the preprint server for biology 0 38014033

Missed literature

Know a paper Affinage missed for MED4? Flag it for the maintainers and the community.

No submissions yet.