Affinage

AFF4

AF4/FMR2 family member 4 · UniProt Q9UHB7

Length
1163 aa
Mass
127.5 kDa
Annotated
2026-06-09
46 papers in source corpus 26 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AFF4 is the central intrinsically disordered scaffold of the Super Elongation Complex (SEC), an assembly that releases promoter-proximally paused RNA Polymerase II to drive productive transcriptional elongation (PMID:20159561, PMID:37609817). Along its disordered axis, AFF4 uses distinct short interaction motifs to directly recruit P-TEFb (through CycT1), ELL2, and ENL/AF9, integrating these elongation factors into a single complex acting on the same polymerase (PMID:20471948, PMID:23251033). Crystallographic analysis shows AFF4 meanders over the CycT1 surface without contacting CDK9, binding through a surface distinct from the CDK9 and Hexim1 sites (PMID:23471103, PMID:24985467), while its C-terminal homology domain (CHD) and a dimerization domain (THD) mediate AFF4 homodimerization and AFF1–AFF4 heterodimerization, with dimerization being essential for HIV-1 proviral transactivation but dispensable for binding other SEC subunits (PMID:31147444, PMID:32128251). AFF4 is a key cofactor for HIV-1 Tat: it bridges P-TEFb and ELL2 into a bifunctional elongation complex and, by partially ordering the CycT1 Tat-TAR recognition motif, increases the affinity of Tat-P-TEFb for TAR RNA, acting as a selectivity filter that favors SEC assembly over P-TEFb alone (PMID:20471948, PMID:24843025, PMID:27731797). Its activity is tuned by phosphorylation—CDK9 modifies a CHD surface loop to trigger pause release and phosphorylates S388 for PAX2-directed recruitment, while P70S6K phosphorylates S831 in an insulin-dependent manner to enhance ENL/AF9 recruitment to crotonylated histones (PMID:31147444, PMID:41476161, PMID:37063434). Through these activities AFF4 controls discrete transcriptional programs and physically engages cohesin and RNAP2; gain-of-function missense mutations in AFF4 cause CHOPS syndrome (PMID:25730767). Functionally, AFF4 is essential for spermatogenesis via Sertoli-cell transcriptional control (PMID:16024815) and for osteogenic and adipogenic differentiation, the latter through direct transcriptional activation of autophagy genes ATG5 and ATG16L1 (PMID:28955517, PMID:36149892), and it sustains oncogenic transcription of MYC, SOX2 and nucleotide-metabolism genes in bladder and pancreatic cancers (PMID:30659266, PMID:32676121, PMID:37063434). AFF4 acts antagonistically with its paralog AFF1 across the transcription start site to set elongation rate and termination (PMID:37528066).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2002 Medium

    Establishing that AFF4 (MCEF) is a physical partner of P-TEFb placed it within the transcriptional elongation machinery, the first mechanistic anchor for its function.

    Evidence Affinity purification of epitope-tagged CDK9 with protein sequencing and reciprocal co-immunoprecipitation

    PMID:12065898

    Open questions at the time
    • Did not define the binding interface or which P-TEFb subunit is contacted
    • No functional consequence of the interaction shown
  2. 2005 High

    A knockout established a physiological requirement for AFF4 in vivo, showing it is essential for spermatogenesis through somatic-cell transcriptional control.

    Evidence Aff4 knockout mouse with histology and spermatogenesis gene-expression profiling

    PMID:16024815

    Open questions at the time
    • Did not connect the testicular phenotype to SEC scaffolding biochemistry
    • Direct transcriptional targets in Sertoli cells not mapped genome-wide
  3. 2007 Medium

    Mapping the determinants of AFF4 nuclear localization and its repressive effect on Tat-transactivation defined where and how it acts on HIV transcription.

    Evidence EGFP-fusion live-cell imaging with deletion mapping and HIV-1 LTR reporter assays

    PMID:17389929

    Open questions at the time
    • Repression in this overexpression context contrasts with later activation models; context dependence unresolved
    • No interaction-partner mapping
  4. 2010 High

    Identifying AFF4 as a core SEC subunit required for complex stability and for MLL-chimera target gene expression defined its central scaffolding role and disease relevance in leukemia.

    Evidence Affinity purification of MLL chimeras with mass spectrometry and siRNA knockdown transcriptional readouts

    PMID:20159561 PMID:20471948

    Open questions at the time
    • Atomic-level interaction architecture not yet defined
    • How AFF4 selects target genes not addressed
  5. 2012 High

    Systematic mapping of AFF4's short interaction motifs showed it recruits ELL2, ENL/AF9 and P-TEFb along a disordered axis, establishing the architecture of the Tat elongation complex.

    Evidence In vitro pulldowns with truncation/mutation constructs plus in vivo co-IP and binding-site analysis

    PMID:23251033

    Open questions at the time
    • High-resolution structures of individual interfaces not yet available
    • Stoichiometry and dynamics of full assembly unresolved
  6. 2014 High

    A series of crystal and integrative structures of Tat·AFF4·P-TEFb and the TAR-bound complex revealed how AFF4 contacts CycT1 (but not CDK9), orders the Tat-TAR recognition motif, and acts as a selectivity filter that enhances TAR binding.

    Evidence X-ray crystallography, cryo-EM/SAXS/HDX integrative structures, interface mutagenesis and transcription assays

    PMID:23471103 PMID:24727379 PMID:24843025 PMID:24985467 PMID:27731797

    Open questions at the time
    • Structures focus on the HIV Tat complex; cellular-target SEC architecture less defined
    • Conformational dynamics during pause release not fully captured
  7. 2015 High

    Gain-of-function AFF4 mutations causing CHOPS syndrome, with altered genome-wide AFF4/cohesin/RNAP2 binding, linked SEC dysregulation to human disease and connected the SEC physically to cohesin.

    Evidence Exome sequencing, ChIP-seq, and co-IP demonstrating SEC-cohesin-RNAP2 interaction

    PMID:25730767

    Open questions at the time
    • Mechanism by which mutant AFF4 alters cohesin distribution not resolved
    • Causal target genes of the syndrome phenotype not pinpointed
  8. 2017 High

    High-resolution structure of the ELL2-AFF4 (ELLBow) interface and functional studies in mesenchymal stem cells extended AFF4 mechanism to both SEC assembly detail and tissue differentiation.

    Evidence 2.0 Å crystallography with mutagenesis; siRNA/overexpression with ChIP at ID1 and BMP2 reporter assays in MSCs

    PMID:28134250 PMID:28955517

    Open questions at the time
    • Whether ELLBow interface mutations affect non-HIV transcription not tested
    • Osteogenic role mechanistically separate from SEC scaffolding not fully established
  9. 2019 High

    Structural definition of the AFF4-CHD as a dimerization, nucleic-acid-binding and CDK9 substrate module, plus identification of FUS as a condensate-forming regulator, refined how AFF4 oligomerizes and is regulated.

    Evidence 2.2 Å crystallography, dimerization and fluorescence anisotropy assays, in vitro CDK9 kinase assay; co-localization, ChIP and HIV latency models for FUS

    PMID:31147444 PMID:31238957

    Open questions at the time
    • Physiological consequence of CHD nucleic-acid binding not defined
    • FUS data are single-lab and Medium confidence
  10. 2020 High

    Structure of the AFF4-THD dimerization domain and point mutants showed dimerization is essential for HIV-1 transactivation yet dispensable for other SEC-subunit contacts, separating two AFF4 functions.

    Evidence 2.4 Å crystallography, site-directed mutagenesis, co-IP and HIV-1 transactivation reporter assays

    PMID:32128251 PMID:32139123

    Open questions at the time
    • Why dimerization is selectively required for proviral transactivation not mechanistically explained
    • Role of dimerization at cellular target genes untested
  11. 2022 High

    Conditional knockout and direct binding to ATG5/ATG16L1 established AFF4 as a transcriptional driver of autophagy genes required for adipocyte development, broadening its differentiation roles.

    Evidence Co-IP, conditional Aff4 knockout mice, and epistasis rescue with ATG5/ATG16L1

    PMID:36149892

    Open questions at the time
    • Whether ATG5/ATG16L1 activation occurs through canonical SEC elongation not directly shown
    • Tissue specificity of this program unexplained
  12. 2024 High

    Genome-wide dissection showed AFF4 and AFF1 act antagonistically across the TSS to control elongation rate and termination, and that AFF4 promotes Ser2-P Pol II and pause release, defining its quantitative role in elongation control.

    Evidence ChIP-seq, PRO-seq, RNA-seq and CUT&Tag with siRNA knockdown of both paralogs

    PMID:37528066 PMID:37609817

    Open questions at the time
    • What distinguishes AFF1- versus AFF4-favored genes is unresolved
    • Mechanism of mutual chromatin-level antagonism unclear
  13. 2024 Medium

    MeCP2 was shown to directly bind AFF4 and recruit the SEC to synaptic genes, implicating AFF4-dependent elongation in MeCP2 (Rett-related) biology.

    Evidence Co-IP in human cells and mouse brain, direct binding assay, ChIP and Drosophila genetic screen (preprint)

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Whether MeCP2-AFF4 recruitment is direct or via additional factors needs further validation
  14. 2025 High

    Identification of P70S6K-mediated AFF4 S831 phosphorylation linking insulin signaling to ENL/AF9 recruitment onto crotonylated histones established a signaling-to-elongation axis relevant to insulin-resistant bone.

    Evidence Phosphoproteomics, in vitro kinase assay, ChIP for ENL/AF9, and zebrafish/osteoblast loss-of-function

    PMID:41476161

    Open questions at the time
    • Full set of S831-dependent target genes not mapped
    • How phosphorylation alters the AFF4-ENL/AF9 interface structurally not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AFF4 selects its specific target gene sets across distinct tissues and disease states—and how its many phosphorylation and dimerization states are integrated to determine which elongation programs are activated—remains unresolved.
  • No unifying model linking AFF4 post-translational states to target-gene specificity
  • Relationship between SEC scaffolding and tissue-specific differentiation programs incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0003723 RNA binding 2 GO:0003677 DNA binding 1
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3
Partners
AFF1ATG5CCNT1ELL2FUSMECP2MLLT1MLLT3
Complex memberships
P-TEFbSuper Elongation Complex (SEC)Tat-AFF4-P-TEFb-TAR complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 AFF4 is a core component of the Super Elongation Complex (SEC), which includes ELL, P-TEFb, and other factors. AFF4 is required for SEC stability and proper transcription by poised RNA polymerase II in metazoans. Knockdown of AFF4 in leukemic cells reduces MLL chimera target gene expression. Affinity purification of MLL chimeras followed by mass spectrometry identification of SEC components; siRNA knockdown with gene expression readout Molecular cell High 20159561
2010 AFF4 bridges P-TEFb and ELL2 into a bifunctional elongation complex that greatly activates HIV-1 transcription. Through scaffolding functions of both Tat and AFF4, P-TEFb and ELL2 cooperate on the same RNA polymerase II. Without Tat, AFF4 can mediate the ELL2-P-TEFb interaction inefficiently; Tat overcomes this by bringing more ELL2 to P-TEFb and stabilizing ELL2 in a process requiring active P-TEFb. Sequential affinity-purification, Co-IP, in vitro binding assays, transcription reporter assays Molecular cell High 20471948
2002 MCEF (AFF4) was identified as a binding partner of P-TEFb (CDK9/CyclinT1) by affinity purification from stably transfected cells expressing epitope-tagged CDK9; antisera against recombinant MCEF specifically immunoprecipitated P-TEFb. Affinity purification of P-TEFb complex followed by protein sequencing; co-immunoprecipitation Journal of biomedical science Medium 12065898
2012 AFF4 acts as the central scaffold of the HIV-1 Tat elongation complex, recruiting ELL2, ENL/AF9, and P-TEFb through direct interactions with short hydrophobic regions along its structurally disordered axis. CycT1, ELL2, and ENL/AF9 act as bridging components linking the complex to P-TEFb and the PAF complex. Binding sites were mapped both in vitro and in vivo. In vitro binding mapping (pulldowns with truncation/mutation constructs), in vivo co-IP, structural analysis of binding sites Proceedings of the National Academy of Sciences of the United States of America High 23251033
2013 Crystal structure of AFF4 in complex with P-TEFb (CDK9/CycT1) revealed that AFF4 meanders over the surface of CycT1 but makes no stable contacts with CDK9. AFF4 is positioned to make direct contacts with HIV Tat, and Tat enhances P-TEFb affinity for AFF4. Interface mutations in AFF4 reduced CycT1 binding and AFF4-dependent transcription. X-ray crystal structure determination of tripartite complex; interface mutagenesis; transcription assays eLife High 23471103
2014 Crystal structure of quaternary Tat-P-TEFb-AFF4 complex showed Tat and AFF4 fold on the CycT1 surface and interact directly. AFF4 binding partially orders the CycT1 Tat-TAR recognition motif (TRM) and increases the affinity of Tat-P-TEFb for TAR RNA 30-fold. Interface mutations in AFF1 reduced Tat-AFF1 affinity in vivo and Tat-dependent transcription from the HIV promoter. AFF4 acts as a two-step filter to increase selectivity of Tat and TAR for SECs over P-TEFb alone. X-ray crystal structure of quaternary complex; in vivo affinity assays with interface mutants; transcription reporter assays eLife High 24843025
2014 Crystal structure of Tat·AFF4·P-TEFb complex revealed that Tat binding to AFF4·P-TEFb causes concerted structural changes in AFF4 via a shift of helix H5' of CycT1 and the α-3(10) helix of AFF4. The Tat-TAR recognition motif (TRM) in CycT1 interacts with both Tat and AFF4, exposing arginine side chains for TAR RNA binding. Structural modeling suggests AFF1 and AFF4 are preferred over AFF2/3 for interaction with Tat·P-TEFb. X-ray crystallography of Tat·AFF4·P-TEFb complex Cell cycle (Georgetown, Tex.) High 24727379
2015 Gain-of-function missense mutations in AFF4 cause CHOPS syndrome. Transcriptome and ChIP-seq analyses demonstrated altered genome-wide binding of AFF4, cohesin, and RNAP2 in CHOPS and Cornelia de Lange syndrome (CdLS). Direct molecular interaction between the SEC, cohesin, and RNAP2 was demonstrated, functionally linking the super elongation complex and cohesin. Exome sequencing; ChIP-seq; co-immunoprecipitation to demonstrate SEC-cohesin-RNAP2 interaction Nature genetics High 25730767
2016 Cryo-EM/integrative structure of the HIV-1 TAR-Tat-AFF4-CDK9-CycT1 complex at 5.9 Å resolution showed TAR central loop contacts the CycT1 TRM and the second Tat Zn2+-binding loop. HDX showed AFF4 helix 2 is stabilized in the TAR complex despite not touching RNA, explaining how AFF4 enhances TAR binding to the SEC 50-fold. The Tat ARM enters the TAR major groove between the bulge and central loop. Cryo-EM structure; hydrogen-deuterium exchange (HDX); RNA SHAPE; SAXS; functional transcription assays eLife High 27731797
2017 Crystal structure (2.0 Å) of ELL2 C-terminal domain bound to its 50-residue binding site on AFF4 (ELLBow) revealed ELL2 has an arch-shaped fold similar to tight junction protein occludin. The ELLBow consists of an N-terminal helix followed by an extended hairpin (elbow joint) occupying the concave surface of ELL2. The AFF4-ELL2 interface surface is important for ELL2 promotion of HIV-1 Tat-mediated proviral transcription. X-ray crystallography at 2.0 Å; mutagenesis; transcription reporter assays Nature communications High 28134250
2017 AFF4 depletion in MSCs inhibits osteogenic differentiation (decreased ALP activity, mineralization, osteogenic gene expression), while AFF4 overexpression enhances it. AFF4 is enriched at the promoter region of ID1, and AFF4 knockdown blunts BMP2-induced BRE luciferase activity and SP7/ALP expression. siRNA knockdown; lentiviral overexpression; ChIP at ID1 promoter; luciferase reporter assay; in vivo MSC-mediated bone formation Bone research Medium 28955517
2019 X-ray crystal structure of AFF4 C-terminal homology domain (CHD) at 2.2 Å revealed a novel eight-helix domain distantly related to tetratricopeptide repeat motifs. AFF4-CHD mediates AFF4 homodimerization and AFF1-AFF4 heterodimerization. Fluorescence anisotropy experiments showed AFF4-CHD interacts with both RNA and DNA in vitro. A surface loop in AFF4-CHD was identified as a substrate for CDK9, which triggers release of Pol II from promoter-proximal pausing. X-ray crystallography at 2.2 Å; biochemical dimerization assays; fluorescence anisotropy; in vitro CDK9 kinase assay The Journal of biological chemistry High 31147444
2020 Crystal structure of AFF4-THD (TPRL with Handle Region Dimerization Domain) at 2.4 Å revealed the α4, α5, and α6 helices of one AFF4-THD mediate dimer formation packing against equivalent regions of the second molecule. Single mutations F1014A or Y1096A of AFF4 impair dimer formation. AFF4 dimerization is essential for transactivation of HIV-1 provirus but mutations of AFF1/4 dimerization residues have no effect on interaction with other SEC subunits. X-ray crystallography at 2.4 Å; site-directed mutagenesis; co-IP for SEC subunit interactions; HIV-1 transactivation reporter assay Cell discovery High 32128251
2007 MCEF (AFF4) localizes exclusively to the nucleus. Three distinct protein sequences encoded by three separate exons mediate nuclear localization. Ectopic expression of MCEF represses HIV-1 LTR-directed RNA Pol II transcription at the level of Tat-transactivation. MCEF-EGFP fusion protein live cell imaging; 20 deletion mutant constructs; HIV-1 LTR reporter transcription assay International journal of biological sciences Medium 17389929
2005 AF5q31 (AFF4) knockout mice show male infertility with azoospermia due to arrest of spermiogenesis. AFF4 is preferentially expressed in Sertoli cells. Knockout mice display severely impaired expression of protamine 1, protamine 2, and transition protein 2 and increased apoptosis in seminiferous tubules, indicating AFF4 functions as a transcriptional regulator in testicular somatic cells essential for male germ cell differentiation. Knockout mouse model; histological analysis; gene expression analysis of spermatogenesis genes; cell-type-specific expression profiling Molecular and cellular biology High 16024815
2012 AFF4 expression in hypothalamic neurons is induced by ghrelin and fasting. AFF4 overexpression specifically induces AMPKα2 subunit expression and increases AMPKα2 promoter activity. AFF4 also increases phosphorylation of acetyl-CoA carboxylase α (ACCα) downstream of AMPK. Ghrelin-induced AMPKα2 expression and ACCα phosphorylation in the late phase of activation were attenuated by AFF4 siRNA knockdown. Overexpression and siRNA knockdown in hypothalamic neuronal GT1-7 cells; promoter luciferase assay; Western blot for phosphorylation The Journal of biological chemistry Medium 22528490
2019 FUS (fused in sarcoma) physically interacts with AFF4 in cells and forms nuclear punctuated condensates with AFF4, which are disrupted by aliphatic alcohol treatment. FUS inhibits activation of HIV transcription by AFF4 and ELL2. FUS depletion elevates occupancy of AFF4 and Cdk9 on the viral promoter, genome-wide FUS knockdown leads to increased AFF4 and Cdk9 occupancy on gene promoters, and FUS knockout delays HIV entry into latency. Co-localization (live cell imaging); ChIP for AFF4/Cdk9 occupancy; siRNA/CRISPR knockout; HIV latency model; transcription assays Retrovirology Medium 31238957
2019 METTL3-mediated m6A modification directly targets AFF4 mRNA in bladder cancer cells. AFF4 binds to the MYC promoter and promotes MYC expression, operating as part of an AFF4/NF-κB/MYC signaling network downstream of METTL3-mediated m6A modification. m6A sequencing; m6A methylated RNA immunoprecipitation qRT-PCR; ChIP for AFF4 at MYC promoter; siRNA knockdown with gene expression readout Oncogene Medium 30659266
2020 AFF4 regulates m6A-dependent expression and promotes SOX2 and MYC transcription in bladder cancer stem cells. AFF4 binds to promoter regions of SOX2 and MYC to sustain their transcription; AFF4 knockdown phenocopies METTL3 ablation and diminishes tumor-initiating capability in vivo. siRNA knockdown; ChIP at SOX2 and MYC promoters; xenograft tumor-initiating assays; sphere-forming and ALDH activity assays Stem cells international Medium 32676121
2022 AFF4 regulates autophagy during adipogenesis by directly binding to autophagy-related proteins ATG5 and ATG16L1 and promoting their transcription. Adipose-specific Aff4 knockout mice have impaired adipocyte development and white fat depot formation. Depleting ATG5 or ATG16L1 abrogates adipogenesis in AFF4-overexpressing cells, while overexpression of ATG5/ATG16L1 rescues impaired adipogenesis in Aff4-knockout cells. Co-immunoprecipitation (AFF4-ATG5/ATG16L1 interaction); siRNA knockdown; lentiviral overexpression; Fabp4-cre Aff4 conditional knockout mice; rescue experiments PLoS genetics High 36149892
2024 AFF4 and AFF1 function antagonistically at transcription start sites: AFF4 is enriched downstream of the TSS while AFF1 binds upstream. AFF4 disruption causes slow elongation and early termination in a subset of AFF4-bound active genes; AFF1 deletion leads to fast elongation and transcriptional readthrough in the same gene subset. AFF1 knockdown increases AFF4 levels at chromatin and vice versa. ChIP-seq; PRO-seq; RNA-seq; CUT&Tag; siRNA knockdown of AFF1 and AFF4 Journal of molecular cell biology High 37528066
2023 AFF4 knockdown in HEL cells decreases cellular levels and global chromatin occupancy of CTD serine 2 phosphorylated Pol II. AFF4 promotes pause release likely by facilitating P-TEFb binding to Pol II. AFF4 loss increases promoter-proximal pause of Pol II on heat shock and thousands of non-heat shock genes. ChIP-seq (CTD Ser2-P Pol II); PRO-seq; CUT&Tag; RNA-seq; RNA interference knockdown Yi chuan = Hereditas Medium 37609817
2025 P70S6K phosphorylates AFF4 at S831 in an insulin-dependent manner, and this phosphorylation is attenuated in aged, insulin-resistant bone. Phosphorylation of S831 in AFF4 increases recruitment of chromatin remodelers ENL/AF9 to crotonylated histone via the YEATS domain, promoting gene-specific transcriptional elongation activation. In insulin-resistant osteoblasts, AFF4 S831 phosphorylation is defective and associated with reduced transcriptional elongation at discrete genomic locations. Phosphoproteomic analysis; in vitro kinase assay (P70S6K + AFF4); ChIP for ENL/AF9 at specific loci; zebrafish functional genomic screen; loss-of-function experiments in osteoblasts Nature communications High 41476161
2024 MeCP2 directly binds AFF4 (the SEC scaffold) via the MeCP2 transcriptional repression domain. Loss of MeCP2 in mouse cortex reduces AFF4 binding at a subset of genes involved in synaptic function, which also show the strongest decrease in RNA Pol II genebody binding. MeCP2 physically interacts with the SEC in human cells and mouse brain. Co-immunoprecipitation (human cells and mouse brain); direct binding assay (MeCP2-AFF4); ChIP for AFF4 and Pol II; Drosophila genetic screen for SEC modifiers of MeCP2 phenotypes bioRxivpreprint Medium
2027 AFF4 regulates NFIC transcription during odontogenic differentiation in dental pulp cells. AFF4 depletion decreases ALP activity and odontogenic gene expression; overexpression of NFIC rescues restricted differentiation in AFF4-depleted cells. siRNA knockdown; lentiviral overexpression; ALP activity and mineralization assays; rescue experiment with NFIC overexpression Biochemical and biophysical research communications Medium 32139123
2014 A cyclin T1 mutant (V107E) that cannot bind Hexim1 or CDK9 and cannot assemble on HIV TAR or 7SK snRNA retains strong binding to AFF4, demonstrating that AFF4 binding to CycT1 is mediated by a distinct surface from CDK9 and Hexim1 binding sites. This mutant enforces HIV transcription repression, demonstrating the functional importance of the AFF4-CycT1 interaction for transcription activation. Site-directed mutagenesis of CycT1; co-immunoprecipitation/binding assays; HIV transcription reporter assays; T cell latency model Retrovirology Medium 24985467
2023 AFF4 promotes expression of HPRT1 and IMPDH2 (nucleotide metabolism enzymes) in pancreatic ductal carcinoma cells. CDK9 mediates AFF4 phosphorylation at S388, which is required for PAX2-mediated recruitment of AFF4 to drive HPRT1 and IMPDH2 expression. Xenograft studies confirmed HPRT1 and IMPDH2 function genetically downstream of AFF4. RNA-seq; CUT&Tag (AFF4 chromatin occupancy); xenograft rescue assays; phosphorylation assay International journal of biological sciences Medium 37063434

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Molecular cell 480 20159561
2010 HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Molecular cell 336 20471948
2019 The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network. Oncogene 327 30659266
2015 Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics 116 25730767
1999 AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Proceedings of the National Academy of Sciences of the United States of America 103 10588740
2012 HIV-1 Tat recruits transcription elongation factors dispersed along a flexible AFF4 scaffold. Proceedings of the National Academy of Sciences of the United States of America 79 23251033
2013 The AFF4 scaffold binds human P-TEFb adjacent to HIV Tat. eLife 75 23471103
2014 AFF4 binding to Tat-P-TEFb indirectly stimulates TAR recognition of super elongation complexes at the HIV promoter. eLife 51 24843025
2014 Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4. Cell cycle (Georgetown, Tex.) 50 24727379
2020 The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells. Stem cells international 48 32676121
2019 CircRNA AFF4 promotes osteoblast cells proliferation and inhibits apoptosis via the Mir-7223-5p/PIK3R1 axis. Aging 46 31848327
2016 Insights into HIV-1 proviral transcription from integrative structure and dynamics of the Tat:AFF4:P-TEFb:TAR complex. eLife 45 27731797
2002 MCEF, the newest member of the AF4 family of transcription factors involved in leukemia, is a positive transcription elongation factor-b-associated protein. Journal of biomedical science 43 12065898
2021 Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis. Cell death & disease 41 34145212
2017 AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs. Bone research 39 28955517
2018 AFF4 promotes tumorigenesis and tumor-initiation capacity of head and neck squamous cell carcinoma cells by regulating SOX2. Carcinogenesis 32 29741610
2017 Structural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription. Nature communications 32 28134250
2019 Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization. The Journal of biological chemistry 30 31147444
2005 Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia. Molecular and cellular biology 26 16024815
2019 Long noncoding RNA ZFPM2-AS1 is involved in lung adenocarcinoma via miR-511-3p/AFF4 pathway. Journal of cellular biochemistry 23 31692047
2002 A novel infant acute lymphoblastic leukemia cell line with MLL-AF5q31 fusion transcript. Leukemia 20 12399976
2021 MiR-425-5p accelerated the proliferation, migration, and invasion of ovarian cancer cells via targeting AFF4. Journal of ovarian research 19 34686190
2020 AFF4 regulates osteogenic differentiation of human dental follicle cells. International journal of oral science 18 32606293
2003 Insertion of MLL sequences into chromosome band 5q31 results in an MLL-AF5Q31 fusion and is a rare but recurrent abnormality associated with infant leukemia. Genes, chromosomes & cancer 18 12759932
2019 Fused in sarcoma silences HIV gene transcription and maintains viral latency through suppressing AFF4 gene activation. Retrovirology 16 31238957
2012 Regulation of AMP-activated protein kinase signaling by AFF4 protein, member of AF4 (ALL1-fused gene from chromosome 4) family of transcription factors, in hypothalamic neurons. The Journal of biological chemistry 14 22528490
2023 PI3K/ c-Myc/AFF4 axis promotes pancreatic tumorigenesis through fueling nucleotide metabolism. International journal of biological sciences 13 37063434
2007 MCEF is localized to the nucleus by protein sequences encoded within three distinct exons, where it represses HIV-1 Tat-transactivation of LTR-directed transcription. International journal of biological sciences 11 17389929
2022 AFF4 regulates cellular adipogenic differentiation via targeting autophagy. PLoS genetics 10 36149892
2022 CircRNA AFF4 induced by KDM1A promotes osteogenic differentiation through FNDC5/Irisin pathway. Molecular medicine (Cambridge, Mass.) 10 36401176
2020 Structural and functional insight into the effect of AFF4 dimerization on activation of HIV-1 proviral transcription. Cell discovery 10 32128251
2023 AFF4 regulates osteogenic potential of human periodontal ligament stem cells via mTOR-ULK1-autophagy axis. Cell proliferation 9 37731335
2021 AFF4 facilitates melanoma cell progression by regulating c-Jun activity. Experimental cell research 9 33417923
2014 A single point mutation in cyclin T1 eliminates binding to Hexim1, Cdk9 and RNA but not to AFF4 and enforces repression of HIV transcription. Retrovirology 9 24985467
2024 Distinct roles of two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA polymerase II transcription elongation. Journal of molecular cell biology 6 37528066
2024 N6-methyladenosine-modified circCDK14 promotes ossification of the ligamentum flavum via epigenetic modulation by targeting AFF4. Cellular and molecular life sciences : CMLS 6 39414635
2020 AFF4 enhances odontogenic differentiation of human dental pulp cells. Biochemical and biophysical research communications 6 32139123
2025 AFF4 promotes tumor progression and cisplatin resistance by modulating the PTEN/PI3K/AKT/mTOR axis to accelerate glycolysis in lung adenocarcinoma. Cell & bioscience 5 40790766
2021 Identification of the transcription factor, AFF4, as a new target of miR-203 in CNS. International journal of biological macromolecules 4 33878354
2024 The Biological Significance of AFF4: Promoting Transcription Elongation, Osteogenic Differentiation and Tumor Progression. Combinatorial chemistry & high throughput screening 2 37815186
2023 Multiple Genomic Alterations, Including a Novel AFF4::IRF1 Fusion Gene, in a Treatment-Refractory Blastic Plasmacytoid Dendritic-Cell Neoplasm: A Case Report and Literature Review. International journal of molecular sciences 2 38203475
2025 Phosphoproteomics of aged insulin-resistant bone identifies P70S6K phosphorylation of AFF4 as a gene-specific transcriptional regulator. Nature communications 1 41476161
2024 FENDRR represses Bladder Cancer Cell Proliferation, Stemness, Migration, Invasion, and EMT Process by Targeting miR-18a-5p/AFF4 Axis. Biochemical genetics 1 39572480
2025 Cinobufagin regulates the microRNA-149-3p/AFF4 axis to affect the proliferation and apoptosis of cisplatin-resistant ovarian cancer cells. Journal of chemotherapy (Florence, Italy) 0 40432319
2025 Identification of a novel de novo AFF4 variant (c.778A>G) associated with CHOPS syndrome. Intractable & rare diseases research 0 40904637
2023 AFF4 globally affects the release of paused RNA polymerase II in HEL cells. Yi chuan = Hereditas 0 37609817

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