Affinage

SPEN

Msx2-interacting protein · UniProt Q96T58

Length
3664 aa
Mass
402.2 kDa
Annotated
2026-06-10
100 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPEN (SHARP/Mint) is a large RNA-binding transcriptional corepressor that couples sequence- and structure-specific RNA recognition to recruitment of histone-deacetylase-containing corepressor machinery, silencing genes across distinct developmental and chromatin contexts (PMID:11331609, PMID:25915022). It was first identified through its repression domain, which binds the SMRT corepressor and at least five NuRD-complex components including HDAC1/HDAC2, and through an intrinsic RNA-binding domain that engages the SRA lncRNA (PMID:11331609); its tandem RRM3-RRM4 block forms the structural platform for stable lncRNA association (PMID:24748666). Recruitment of corepressor is executed by the SPOC domain, whose conserved positively charged surface docks the acidic C-terminal motif of SMRT/NCoR, establishing SPOC as the universal corepressor-recruitment module of the family (PMID:12897056). In Notch signaling SPEN bridges the DNA-binding factor RBP-Jkappa to HDAC-dependent corepressors—including CtIP/CtBP and ETO—to repress Notch target genes such as HES-1 and Hey1, a function structurally defined by the RBPJ-SHARP-DNA complex and enhanced by Pak1-mediated phosphorylation of the repression domain (PMID:12374742, PMID:16287852, PMID:15824732, PMID:18332109, PMID:30673607). SPEN's most extensively characterized role is in X-chromosome inactivation: it binds Xist lncRNA directly via its RRM domains, is recruited to enhancers and promoters of active X-linked genes immediately upon Xist upregulation, and silences them through its SPOC domain, which is sufficient to mediate silencing when tethered to Xist; SPEN activates HDAC3, excludes RNA Pol II, and acts in parallel to Polycomb/SmcHD1 pathways (PMID:25915022, PMID:26190100, PMID:32025035, PMID:35584662). SPEN additionally functions in vivo as a tumor suppressor that binds ERα and represses its target genes (PMID:26297734), and is required for Xist upregulation by silencing the antisense repressor Tsix (PMID:34853312).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    Established SPEN as a transcriptional repressor by showing it physically bridges the SMRT and NuRD corepressors to RNA-bound steroid receptor coactivators, defining its dual protein- and RNA-interaction logic.

    Evidence Yeast two-hybrid with SMRT bait, co-IP, and reporter assays in mammalian cells

    PMID:11331609

    Open questions at the time
    • Domain boundaries for RNA versus corepressor binding not yet mapped
    • No genome-wide target identification
  2. 2002 High

    Placed SPEN in Notch signaling by identifying it as an RBP-Jkappa corepressor whose HDAC-dependent repression of Notch targets has developmental consequences.

    Evidence Yeast two-hybrid, reporter assays, and Xenopus embryo rescue of Notch-induced neurogenesis defects

    PMID:12374742

    Open questions at the time
    • Structural basis of RBP-Jkappa interaction unresolved
    • Full corepressor composition at promoters not defined
  3. 2003 High

    Defined the SPOC domain at atomic resolution as the universal corepressor-recruitment module, explaining how SPEN docks SMRT/NCoR.

    Evidence 1.8 Å crystal structure of SPOC with structure-based mutagenesis and binding assays

    PMID:12897056

    Open questions at the time
    • Did not test SPOC sufficiency for silencing in a cellular context
    • Affinity for full-length corepressors not quantified
  4. 2005 High

    Expanded the RBP-Jkappa/SHARP corepressor complex by identifying CtIP/CtBP as functional components and showing the repression domain is necessary and sufficient.

    Evidence Reporter assays, co-IP, dominant-negative mutants, and CtBP-deficient cell lines

    PMID:16287852

    Open questions at the time
    • Stoichiometry and assembly order of the complex unknown
    • In vivo relevance in development not addressed here
  5. 2005 High

    Showed SPEN repressor activity is regulated by signaling, mapping Pak1 phosphorylation sites that enhance Notch target repression.

    Evidence In vitro kinase assays, site-directed mutagenesis, siRNA knockdown, and reporter assays

    PMID:15824732

    Open questions at the time
    • Phosphorylation effect on corepressor binding affinity not measured
    • Upstream signals activating Pak1 toward SPEN unknown
  6. 2008 Medium

    Added ETO to the endogenous RBP-Jkappa corepressor complex and showed the leukemogenic AML1/ETO fusion subverts SPEN repression.

    Evidence Reciprocal co-IP, ChIP at endogenous Notch promoters, and knockdown/overexpression

    PMID:18332109

    Open questions at the time
    • Single lab; reciprocal validation limited
    • Mechanism of AML1/ETO derepression not fully resolved
  7. 2014 High

    Resolved how SPEN recognizes lncRNA by determining the RRM3-RRM4 structure and showing it is the platform for stable SRA association.

    Evidence 2.0 Å crystal structure of RRM3-RRM4 with RNA-binding assays and mutagenesis

    PMID:24748666

    Open questions at the time
    • RNA sequence/structure specificity rules incomplete
    • Did not address Xist binding
  8. 2015 High

    Identified SPEN as the direct Xist-binding effector required for X-inactivation silencing and Pol II exclusion, linking its corepressor function to chromosome-wide gene silencing.

    Evidence RAP-MS, RNAi knockdown, ChIP, and RNA FISH

    PMID:25915022

    Open questions at the time
    • Did not resolve whether SPEN acts before or after Xist localization
    • Direct enzymatic readout of HDAC3 activation not shown
  9. 2015 High

    Independent genetic and shRNA screens confirmed Spen as essential for Xist-mediated repression while dispensable for Xist localization, and localized Spen with Xist in the nuclear matrix.

    Evidence Haploid ESC forward genetic screen with gene deletion; pooled shRNA screen with 3D-SIM super-resolution imaging

    PMID:26190100 PMID:26190105

    Open questions at the time
    • Separation of silencing from PRC2 recruitment not fully resolved
    • Molecular events downstream of SPEN recruitment incomplete
  10. 2015 Medium

    Extended SPEN function to cancer by showing it acts as an ERα-binding tumor suppressor that represses estrogen receptor target genes.

    Evidence Co-IP, microarray pathway analysis, and gain/loss-of-function assays in breast cancer cells in vitro and in vivo

    PMID:26297734

    Open questions at the time
    • Direct versus indirect ERα binding not structurally defined
    • Single lab
  11. 2017 Medium

    Connected SPEN transcriptional output to a cellular phenotype, regulation of primary cilia formation and cilia-dependent migration in breast cells.

    Evidence Overexpression/knockdown, cilia immunofluorescence, migration assays, and KIF3A epistasis

    PMID:28877752

    Open questions at the time
    • Transcriptional targets linking SPEN to ciliogenesis not identified
    • Single lab and cell-line dependent
  12. 2019 High

    Provided the structural basis of Notch repression by determining the RBPJ-SHARP-DNA complex and proving the interaction is required for RBPJ-mediated repression.

    Evidence X-ray crystallography, biophysical assays, structure-based mutagenesis, and cell reporter assays

    PMID:30673607

    Open questions at the time
    • How SHARP simultaneously engages corepressors and RBPJ on chromatin not visualized
    • Single lab
  13. 2020 High

    Defined SPEN as the in vivo orchestrator of XCI initiation, mapped its recruitment to active enhancers/promoters, identified its protein partners, and showed the SPOC domain alone is sufficient for silencing.

    Evidence Conditional knockout mouse, auxin-inducible degron, ChIP-seq, RNA-seq, mass spectrometry, and SPOC tethering assays

    PMID:32025035

    Open questions at the time
    • Mechanism distinguishing initiation versus dispensability in maintenance not fully resolved
    • Stoichiometry of partner complexes at silenced loci unknown
  14. 2020 High

    Revealed an RNA-surveillance role: SPEN recognizes ERV RNAs structurally mimicking the Xist A-repeat via its RRMs, with the two RNAs competing for binding.

    Evidence RNA immunoprecipitation, ATAC-seq, ChIP-seq, competitive binding, and ERV-insertion rescue of Xist silencing

    PMID:32379046

    Open questions at the time
    • Breadth of endogenous RNA targets recognized by SPEN RRMs unknown
    • Single lab
  15. 2021 High

    Placed SPEN upstream of Xist by showing it silences the antisense Tsix promoter, a step required for Xist upregulation.

    Evidence Spen knockout ESC differentiation, RNA FISH, and Tsix-deletion epistasis rescue

    PMID:34853312

    Open questions at the time
    • Direct SPEN occupancy at Tsix not shown here
    • Relationship to SPEN's later silencing role at Xist-coated genes unresolved
  16. 2021 Medium

    Established an in vivo physiological role in heart development, with SPEN controlling cardiac function through Connexin 43.

    Evidence Zebrafish morpholino knockdown, cardiac transcriptome profiling, cx43 rescue, and genetic epistasis

    PMID:33549680

    Open questions at the time
    • Whether SPEN directly represses or activates a cx43 regulator unclear
    • Morpholino approach; single lab
  17. 2022 High

    Showed SPEN amplifies its own abundance across the inactive X through concentration-dependent homotypic assemblies and feeds back to constrain Xist levels.

    Evidence ChIRP-seq, quantitative imaging, SHARP assembly assays, and Xist overexpression

    PMID:35301492

    Open questions at the time
    • Molecular driver of homotypic assembly not defined
    • Generality of feedback beyond XCI unknown
  18. 2022 High

    Demonstrated SPEN and Polycomb/SmcHD1 silencing pathways operate in parallel rather than sequentially, using a separation-of-function mutant.

    Evidence SPEN separation-of-function mutation, conditional knockout, SmcHD1 knockout, RNA-seq, ChIP-seq

    PMID:35584662

    Open questions at the time
    • How SPEN and SmcHD1 partition target genes unresolved
    • Single lab
  19. 2024 High

    Extended SPEN function to human development by showing XIST-SPEN mediates X-chromosome dampening in naive ESCs before full inactivation.

    Evidence XIST and SPEN knockout/knockdown in naive human ESCs with ChIP-seq and RNA-seq

    PMID:38834912

    Open questions at the time
    • Mechanistic distinction between dampening and full silencing not defined
    • Human-specific partners not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SPEN's intrinsic RNA-binding specificity, SPOC-corepressor docking, and concentration-dependent self-assembly are integrated into a single quantitative model of context-selective silencing remains unresolved.
  • No unified biophysical model linking RNA recognition to corepressor output
  • Enzymatic step downstream of HDAC3 activation not directly measured
  • Determinants selecting Notch versus XCI versus ERα contexts unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Partners
CTBPCTIPESR1ETOHDAC3PAK1RBPJSMRT/NCOR
Complex memberships
NCoR/SMRT complexNuRD complexRBP-Jkappa/SHARP corepressor complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SHARP (SPEN) was identified as a novel transcriptional repressor through yeast two-hybrid screening using SMRT as bait. The SHARP repression domain directly interacts with SMRT and at least five members of the NuRD complex including HDAC1 and HDAC2. SHARP also binds the steroid receptor RNA coactivator SRA via an intrinsic RNA-binding domain and suppresses SRA-potentiated steroid receptor transcriptional activity. Yeast two-hybrid screen, co-immunoprecipitation, cotransfection reporter assays Genes & development High 11331609
2002 SHARP (SPEN) was identified as an RBP-Jkappa/CBF-1-interacting corepressor in Notch signaling. SHARP-mediated repression of Notch target genes (HES-1 promoter) was sensitive to the HDAC inhibitor TSA and facilitated by SKIP. SHARP repressed Notch-1-mediated transactivation and rescued Notch-1-induced inhibition of primary neurogenesis in Xenopus embryos. Yeast two-hybrid screen, cotransfection reporter assays, Xenopus embryo rescue experiments The EMBO journal High 12374742
2003 The crystal structure of the SPOC domain from SHARP was determined at 1.8 Å resolution. Structure-based mutational analysis revealed that a conserved positively charged surface patch on SPOC mediates interaction with SMRT/NCoR through a highly conserved acidic motif at the C-terminus of SMRT/NCoR, establishing the SPOC domain as the universal corepressor-recruitment module of Spen family proteins. X-ray crystallography, structure-based mutagenesis, binding assays Genes & development High 12897056
2005 The SHARP repression domain is necessary and sufficient for transcriptional repression in the RBP-Jkappa/SHARP corepressor complex. CtIP and CtBP corepressors were identified as novel components of the human RBP-Jkappa/SHARP complex; CtIP binds directly to the SHARP repression domain and CtBP augments SHARP-mediated repression in an HDAC-dependent manner. Transcriptional repression of Notch target gene Hey1 is abolished in CtBP-deficient cells. Cotransfection reporter assays, co-immunoprecipitation, dominant-negative mutants, CtBP-deficient cell lines Molecular and cellular biology High 16287852
2005 SHARP is a physiologic interacting substrate of Pak1 kinase. Pak1 phosphorylates SHARP at Ser3486 and Thr3568 within the SHARP repression domain. This phosphorylation enhances SHARP-mediated repression of Notch target genes; mutation of these sites or inhibition of Pak1 interferes with SHARP-mediated repression. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, siRNA knockdown, reporter assays Oncogene High 15824732
2008 The corepressor ETO directly interacts with SHARP and is part of the endogenous RBP-Jkappa-containing corepressor complex at Notch target gene promoters. ETO augments SHARP-mediated repression in an HDAC-dependent manner; in contrast, the leukemogenic fusion AML1/ETO does not augment SHARP repression and instead derepresses Notch target genes. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, knockdown/overexpression Molecular and cellular biology Medium 18332109
2014 Crystal structure of the RRM domain region (RRM3-RRM4) of human SHARP/SPEN was determined at 2.0 Å resolution. RRM3 and RRM4 interact via a highly conserved interface, and the RRM3-RRM4 block is the main platform mediating stable association with the H12-H13 substructure of the steroid receptor RNA activator (SRA) lncRNA, involving both single- and double-stranded RNA sequences. X-ray crystallography, RNA-binding assays, mutagenesis Nucleic acids research High 24748666
2015 SHARP (SPEN) directly interacts with Xist lncRNA and is required for Xist-mediated transcriptional silencing of the inactive X chromosome. SHARP, which interacts with the SMRT co-repressor that activates HDAC3, is essential for silencing and for the exclusion of RNA Pol II from the inactive X. SHARP and HDAC3 are also required for Xist-mediated recruitment of PRC2 across the X chromosome. RNA antisense purification with quantitative mass spectrometry (RAP-MS), RNAi knockdown, ChIP, RNA FISH Nature High 25915022
2015 A forward genetic screen in haploid mouse ESCs identified Spen as genetically required for gene repression by Xist during X chromosome inactivation. Gene deletion of Spen confirmed its requirement for Xist-mediated gene repression, but Spen is not required for Xist RNA localization or for recruitment of Polycomb protein Ezh2 to the X chromosome. Forward genetic screen (haploid ESC mutagenesis), gene deletion, RNA FISH, ChIP Cell reports High 26190100
2015 shRNA screen identified Spen (along with Rbm15 and Wtap) as required for Xist RNA-mediated gene silencing. Spen co-localizes with Xist RNA within the nuclear matrix subcompartment, consistent with direct interaction, as demonstrated by super-resolution 3D-SIM microscopy. Pooled shRNA screen, super-resolution 3D-SIM microscopy, RNA FISH Cell reports High 26190105
2015 SPEN functions as a tumor suppressor in ERα-expressing breast cancers. SPEN binds ERα in a ligand-independent manner and negatively regulates the transcription of ERα target genes. SPEN overexpression sensitizes hormone receptor-positive breast cancer cells to apoptotic effects of tamoxifen but has no effect on fulvestrant responsiveness. Co-immunoprecipitation, in vitro and in vivo functional assays, microarray-based pathway analyses, loss-of-function and gain-of-function experiments Cancer research Medium 26297734
2017 SPEN regulates primary cilia formation in breast cancer cells. SPEN re-expression in SPEN-deficient T47D cells restored primary cilia, while SPEN knockdown in MCF10A and Hs578T cells decreased primary cilia levels. SPEN regulates cell migration in breast cells only in those harboring primary cilia, and KIF3A silencing (critical for primary cilia) partially reverses SPEN's effects on migration. Overexpression/knockdown, immunofluorescence microscopy for cilia, migration assays, DNA microarrays Breast cancer research : BCR Medium 28877752
2019 The crystal structure of RBPJ bound to the corepressor SHARP and DNA was determined, revealing SHARP's mode of binding to RBPJ. Structure-based RBPJ mutants deficient for SHARP binding are incapable of repressing transcription of Notch-responsive genes in cells, demonstrating that the RBPJ-SHARP interaction is required for RBPJ-mediated transcriptional repression. X-ray crystallography, biophysical assays, site-directed mutagenesis, reporter assays in cells Cell reports High 30673607
2020 SPEN is a key orchestrator of X chromosome inactivation (XCI) in vivo. SPEN is essential for initiating gene silencing on the X chromosome in preimplantation embryos and ESCs, but dispensable for XCI maintenance in neural progenitors. SPEN is recruited to the X chromosome immediately upon Xist upregulation and targets enhancers and promoters of active genes. The SPOC domain is defined as the major effector of SPEN's gene-silencing function; tethering SPOC to Xist RNA alone is sufficient to mediate gene silencing. SPEN's protein partners include NCoR/SMRT, m6A RNA methylation machinery, NuRD complex, RNA Pol II, and factors regulating transcription initiation and elongation. Conditional knockout mouse model, auxin-inducible degron system, ChIP-seq, RNA-seq, mass spectrometry for protein partners, SPOC domain tethering assays Nature High 32025035
2020 Spen binds directly to endogenous retroviral (ERV) RNAs that show structural similarity to the A-repeat of Xist, performing a surveillance role recruiting chromatin silencing machinery to retroviral loci. Spen loss activates ERV elements with gain of chromatin accessibility and active histone modifications. ERV RNA and Xist A-repeat bind the RRM domains of Spen in a competitive manner. Insertion of an ERV into an A-repeat-deficient Xist rescues Xist-Spen binding and restores local gene silencing in cis. RNA immunoprecipitation, ATAC-seq, ChIP-seq, RNA-seq, competitive binding assays, ERV insertion rescue experiments eLife High 32379046
2021 SPEN plays an important role in initiation of X chromosome inactivation upstream of Xist upregulation. Spen-null female ESCs are defective in Xist upregulation upon differentiation. SPEN-mediated silencing of the Tsix promoter (antisense repressor of Xist) is required for Xist upregulation; failed Xist upregulation in Spen-/- ESCs is rescued by concomitant removal of Tsix. Spen knockout ESCs, differentiation assays, RNA FISH, Tsix deletion epistasis Nature communications High 34853312
2021 Spen deficiency in zebrafish leads to progressive cardiac dysfunction including bradycardia, atrioventricular block, and heart chamber fibrillation. SPEN controls cardiac function through regulation of Connexin 43 (Cx43) expression; ectopic Cx43 overexpression in Spen-deficient embryos rescues cardiac contractile function and suppresses arrhythmia. Sub-phenotypic co-injection of spen and cx43 morpholinos produces supra-additive pathological effects. Morpholino knockdown in zebrafish, cardiac-specific transcriptome profiling, rescue by cx43 overexpression, genetic epistasis Journal of molecular and cellular cardiology Medium 33549680
2022 Xist drives non-stoichiometric recruitment of SHARP/SPEN to amplify its abundance across the inactive X, including at regions not directly occupied by Xist. This amplification is achieved through concentration-dependent homotypic assemblies of SHARP on the X and is required for chromosome-wide silencing. SPEN (through SHARP) suppresses production of Xist RNA itself, constraining overall Xist levels and restricting its spread beyond the X. ChIRP-seq, quantitative imaging, SHARP condensate/assembly assays, Xist overexpression experiments Nature structural & molecular biology High 35301492
2022 SPEN and Polycomb pathways function in parallel (not sequentially) to establish X-linked gene silencing. Using a SPEN separation-of-function mutation that uncouples SPEN's role in Xist RNA localization from gene silencing, differentiation-dependent recruitment of SmcHD1 is shown to be required for silencing many X-linked genes independently of SPEN. Separation-of-function mutation, SPEN conditional knockout, SmcHD1 knockout, RNA-seq, ChIP-seq Cell reports High 35584662
2024 XIST triggers deposition of polycomb-mediated repressive histone modifications and dampens transcription of most X-linked genes in a SPEN-dependent manner in human preimplantation-stage naive ESCs, demonstrating that XIST-SPEN-mediated X chromosome dampening occurs before full X chromosome inactivation. XIST and SPEN knockout/knockdown in naive human ESCs, ChIP-seq, RNA-seq Nature structural & molecular biology High 38834912
2007 Mint/SHARP (mouse Spen) interacts with the Notch-signaling mediator RBP-J and suppresses Notch signaling through RBP-J during splenic B-lymphocyte development. Conditional knockout of Mint in postnatal mice revealed that Mint deficiency causes severe hypoplasia in postnatal brain, suggesting a role in neuronal cell survival. Conditional knockout (Cre/loxP), epistasis analysis of Mint and RBP-J during B-lymphocyte development Genesis (New York, N.Y. : 2000) Medium 17457934

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. Nature 911 25915022
2020 Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19. Cell 473 33171100
1992 SRY, like HMG1, recognizes sharp angles in DNA. The EMBO journal 401 1425584
2020 The auxin-inducible degron 2 technology provides sharp degradation control in yeast, mammalian cells, and mice. Nature communications 382 33177522
1992 Membrane properties of dentate gyrus granule cells: comparison of sharp microelectrode and whole-cell recordings. Journal of neurophysiology 296 1597717
2001 Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. Genes & development 277 11331609
2004 Spontaneous sharp bending of double-stranded DNA. Molecular cell 258 15125838
2002 SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. The EMBO journal 232 12374742
2015 A Pooled shRNA Screen Identifies Rbm15, Spen, and Wtap as Factors Required for Xist RNA-Mediated Silencing. Cell reports 229 26190105
2004 Hippocampal sharp wave bursts coincide with neocortical "up-state" transitions. Learning & memory (Cold Spring Harbor, N.Y.) 213 15576887
2015 Identification of Spen as a Crucial Factor for Xist Function through Forward Genetic Screening in Haploid Embryonic Stem Cells. Cell reports 203 26190100
2014 Mechanisms of sharp wave initiation and ripple generation. The Journal of neuroscience : the official journal of the Society for Neuroscience 200 25143618
2015 Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples. Nature neuroscience 191 26214372
2010 The spen family protein FPA controls alternative cleavage and polyadenylation of RNA. Developmental cell 191 20079695
2001 Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 187 11344311
2020 SPEN integrates transcriptional and epigenetic control of X-inactivation. Nature 162 32025035
2005 RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes. Molecular and cellular biology 151 16287852
2003 A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling. Genes & development 134 12897056
2014 A sharp T-cell antigen receptor signaling threshold for T-cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 132 25136127
1997 Feed-forward and feed-back activation of the dentate gyrus in vivo during dentate spikes and sharp wave bursts. Hippocampus 119 9287083
2007 EEG sharp waves and sparse ensemble unit activity in the macaque hippocampus. Journal of neurophysiology 105 17522177
2022 Xist spatially amplifies SHARP/SPEN recruitment to balance chromosome-wide silencing and specificity to the X chromosome. Nature structural & molecular biology 91 35301492
2017 Mechanisms for Selective Single-Cell Reactivation during Offline Sharp-Wave Ripples and Their Distortion by Fast Ripples. Neuron 89 28641116
2008 Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice. PloS one 86 18648504
2005 Interaction of the Epstein-Barr virus mRNA export factor EB2 with human Spen proteins SHARP, OTT1, and a novel member of the family, OTT3, links Spen proteins with splicing regulation and mRNA export. The Journal of biological chemistry 82 16129689
2012 Likelihood-based selection and sharp parameter estimation. Journal of the American Statistical Association 81 22736876
2021 Cholinergic suppression of hippocampal sharp-wave ripples impairs working memory. Proceedings of the National Academy of Sciences of the United States of America 79 33833054
2018 A novel pyramidal cell type promotes sharp-wave synchronization in the hippocampus. Nature neuroscience 77 29915194
1999 spen encodes an RNP motif protein that interacts with Hox pathways to repress the development of head-like sclerites in the Drosophila trunk. Development (Cambridge, England) 77 10556062
2014 Physiological sharp wave-ripples and interictal events in vitro: what's the difference? Brain : a journal of neurology 76 24390441
2021 SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females. American journal of human genetics 73 33596411
2020 SHARP: hyperfast and accurate processing of single-cell RNA-seq data via ensemble random projection. Genome research 73 31992615
2004 Isolation by distance and sharp discontinuities in gene frequencies: implications for the phylogeography of an alpine insect species, Carabus solieri. Molecular ecology 72 15189211
2004 Sharp-1/DEC2 inhibits skeletal muscle differentiation through repression of myogenic transcription factors. The Journal of biological chemistry 72 15448136
2014 Learning-induced plasticity regulates hippocampal sharp wave-ripple drive. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 24719097
2010 Targeting GSK-3 family members in the heart: a very sharp double-edged sword. Journal of molecular and cellular cardiology 62 21163265
2018 Development and molecular cytogenetic identification of a new wheat-rye 4R chromosome disomic addition line with resistances to powdery mildew, stripe rust and sharp eyespot. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 60 30374527
2003 Insulin induces the expression of the SHARP-2/Stra13/DEC1 gene via a phosphoinositide 3-kinase pathway. The Journal of biological chemistry 59 12796501
2014 Generation of physiological and pathological high frequency oscillations: the role of perisomatic inhibition in sharp-wave ripple and interictal spike generation. Current opinion in neurobiology 56 25128735
2004 The hypoxia-regulated transcription factor DEC1 (Stra13, SHARP-2) and its expression in human tissues and tumours. The Journal of pathology 55 15221940
2020 Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation. eLife 53 32379046
2019 Dissecting the sharp response of a canonical developmental enhancer reveals multiple sources of cooperativity. eLife 50 31223115
2015 The Estrogen Receptor Cofactor SPEN Functions as a Tumor Suppressor and Candidate Biomarker of Drug Responsiveness in Hormone-Dependent Breast Cancers. Cancer research 49 26297734
2022 Apoptosis Induction, a Sharp Edge of Berberine to Exert Anti-Cancer Effects, Focus on Breast, Lung, and Liver Cancer. Frontiers in pharmacology 44 35153781
2017 Disruption of perineuronal nets increases the frequency of sharp wave ripple events. Hippocampus 42 28921856
2017 SPEN, a new player in primary cilia formation and cell migration in breast cancer. Breast cancer research : BCR 41 28877752
2019 Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site. Cell reports 40 30673607
2012 G9a mediates Sharp-1-dependent inhibition of skeletal muscle differentiation. Molecular biology of the cell 40 23087213
2007 Generation of a conditional knockout allele for mammalian Spen protein Mint/SHARP. Genesis (New York, N.Y. : 2000) 39 17457934
2014 The crystal structure of the Split End protein SHARP adds a new layer of complexity to proteins containing RNA recognition motifs. Nucleic acids research 38 24748666
2005 An essential role of Pak1 phosphorylation of SHARP in Notch signaling. Oncogene 38 15824732
2022 Hippocampal sharp wave-ripples and the associated sequence replay emerge from structured synaptic interactions in a network model of area CA3. eLife 37 35040779
2008 ETO, but not leukemogenic fusion protein AML1/ETO, augments RBP-Jkappa/SHARP-mediated repression of notch target genes. Molecular and cellular biology 37 18332109
2023 Inhibitory control of sharp-wave ripple duration during learning in hippocampal recurrent networks. Nature neuroscience 36 37081295
2021 SPEN is required for Xist upregulation during initiation of X chromosome inactivation. Nature communications 36 34853312
2021 Sharp Increase of Problematic Mitogenomes of Birds: Causes, Consequences, and Remedies. Genome biology and evolution 35 34505894
2019 Cell lysis via acoustically oscillating sharp edges. Lab on a chip 35 31720640
2014 Stra13 and Sharp-1, the non-grouchy regulators of development and disease. Current topics in developmental biology 34 25248481
2013 Sharp wave/ripple network oscillations and learning-associated hippocampal maps. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 34 24366138
2022 Reorganization of CA1 dendritic dynamics by hippocampal sharp-wave ripples during learning. Neuron 32 35041805
2009 The hypoxia-regulated transcription factor DEC1 (Stra13, SHARP-2) and its expression in gastric cancer. Omics : a journal of integrative biology 31 19624270
2018 A sharp-edge-based acoustofluidic chemical signal generator. Lab on a chip 30 29668002
2016 The wheat calcium-dependent protein kinase TaCPK7-D positively regulates host resistance to sharp eyespot disease. Molecular plant pathology 30 26720854
2022 User-friendly microfluidic manufacturing of hydrogel microspheres with sharp needle. Biofabrication 29 35193129
2021 Overexpression of TaSTT3b-2B improves resistance to sharp eyespot and increases grain weight in wheat. Plant biotechnology journal 28 34873799
2020 Generation of Sharp Wave-Ripple Events by Disinhibition. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 32913107
2022 Xist-mediated silencing requires additive functions of SPEN and Polycomb together with differentiation-dependent recruitment of SmcHD1. Cell reports 27 35584662
2020 SPEN induces miR-4652-3p to target HIPK2 in nasopharyngeal carcinoma. Cell death & disease 27 32641685
2014 Small ubiquitin-like modifier (SUMO) protein-specific protease 1 de-SUMOylates Sharp-1 protein and controls adipocyte differentiation. The Journal of biological chemistry 27 24942744
2001 Gene structure and chromosomal location of a human bHLH transcriptional factor DEC1 x Stra13 x SHARP-2/BHLHB2. Journal of biochemistry 27 11226878
2021 Subiculum as a generator of sharp wave-ripples in the rodent hippocampus. Cell reports 26 33882307
2007 Sharp melting in DNA-linked nanostructure systems: thermodynamic models of DNA-linked polymers. The journal of physical chemistry. B 26 17616117
2022 Surfaces Containing Sharp Nanostructures Enhance Antibiotic Efficacy. Nano letters 25 35900125
2020 Spen modulates lipid droplet content in adult Drosophila glial cells and protects against paraquat toxicity. Scientific reports 25 33208773
2020 Potential factors influencing replay across CA1 during sharp-wave ripples. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 24 32248778
2023 Sharp cell-type-identity changes differentiate the retrosplenial cortex from the neocortex. Cell reports 23 36881508
2024 XIST dampens X chromosome activity in a SPEN-dependent manner during early human development. Nature structural & molecular biology 22 38834912
2017 A sharp Pif1-dependent threshold separates DNA double-strand breaks from critically short telomeres. eLife 22 28826474
2001 Accidental sharp force fatalities--beware of architectural glass, not knives. Forensic science international 22 11728738
2023 Two coral fluorescent proteins of distinct colors for sharp visualization of cell-cycle progression. Cell structure and function 21 37394513
2016 Pretreatment with β-adrenergic receptor agonists facilitates induction of LTP and sharp wave ripple complexes in rodent hippocampus. Hippocampus 20 27699900
2023 A cell wall invertase modulates resistance to fusarium crown rot and sharp eyespot in common wheat. Journal of integrative plant biology 19 36912577
2023 Hippocampal sharp wave ripples underlie stress susceptibility in male mice. Nature communications 19 37080967
2022 Cell-type-specific silence in thalamocortical circuits precedes hippocampal sharp-wave ripples. Cell reports 19 35905724
2022 Nanotechnology-integrated ferroptosis inducers: a sharp sword against tumor drug resistance. Journal of materials chemistry. B 19 36043505
2013 Effects of μ-opioid receptor modulation on the hippocampal network activity of sharp wave and ripples. British journal of pharmacology 19 23043226
2024 Immunogenic cell death-based oncolytic virus therapy: A sharp sword of tumor immunotherapy. European journal of pharmacology 18 39154830
2021 TaWAK2A-800, a Wall-Associated Kinase, Participates Positively in Resistance to Fusarium Head Blight and Sharp Eyespot in Wheat. International journal of molecular sciences 17 34768923
2018 Sharp-wave ripple features in macaques depend on behavioral state and cell-type specific firing. Hippocampus 17 30371963
2017 An autonomous metabolic role for Spen. PLoS genetics 17 28640815
2015 Spen is required for pigment cell survival during pupal development in Drosophila. Developmental biology 17 25872184
2013 Sharp-1 regulates TGF-β signaling and skeletal muscle regeneration. Journal of cell science 17 24357723
2022 Sharp, localized phase transitions in single neuronal cells. Proceedings of the National Academy of Sciences of the United States of America 16 35165183
2020 Gene-Diet Interactions: Dietary Rescue of Metabolic Effects in spen-Depleted Drosophila melanogaster. Genetics 16 32107279
2020 Elements at the 5' end of Xist harbor SPEN-independent transcriptional antiterminator activity. Nucleic acids research 16 32986830
2020 Cell-fate plasticity, adhesion and cell sorting complementarily establish a sharp midbrain-hindbrain boundary. Development (Cambridge, England) 15 32439756
2019 Impairment of Sharp-Wave Ripples in a Murine Model of Dravet Syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 15 31537705
2022 The two tales of hippocampal sharp-wave ripple content: The rigid and the plastic. Progress in neurobiology 14 36563928
2021 Spen deficiency interferes with Connexin 43 expression and leads to heart failure in zebrafish. Journal of molecular and cellular cardiology 14 33549680
2019 Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone cells via a sharp increase in β-catenin. Bone 14 31751752

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