Affinage

HMGN4

High mobility group nucleosome-binding domain-containing protein 4 · UniProt O00479

Length
90 aa
Mass
9.5 kDa
Annotated
2026-06-10
100 papers in source corpus 2 papers cited in narrative 2 extracted findings
Cross-family judge faithfulness: 2/2 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HMGN4 is a nuclear nucleosome-binding protein of the HMGN family that modulates chromatin and transcription, encoded by an intronless gene at chromosome 6p21.3 and closely related to HMGN2 (PMID:11410162). It localizes to the nucleus and binds nucleosomes (PMID:11410162), and when overexpressed it reshapes the cellular transcription profile—downregulating the tumor suppressors Atm, Atrx, and Brca2, elevating the DNA damage marker γH2AX, and increasing tumorigenicity in colony-formation and xenograft assays; thyroid-targeted transgenic overexpression drives preneoplastic lesions, establishing HMGN4 as an epigenetic potentiator of thyroid oncogenesis (PMID:28186538). Beyond these findings, the molecular details of how HMGN4 binding to nucleosomes effects transcriptional repression of specific tumor suppressors have not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2001 Medium

    Establishing whether HMGN4 is a bona fide member of the nucleosome-binding HMGN family answered where this protein acts and how it engages chromatin.

    Evidence Western blot with a region-specific antibody, HMGN4-GFP fusion live imaging in HeLa cells, and Northern blot tissue profiling

    PMID:11410162

    Open questions at the time
    • No functional consequence of nucleosome binding tested
    • No mapping of genomic binding sites
    • Relationship to other HMGN paralogs at shared sites unresolved
  2. 2017 Medium

    Determining the cellular consequence of HMGN4 dosage showed it functions as an epigenetic factor that represses tumor suppressors and promotes tumorigenesis.

    Evidence Transgenic mouse thyroid overexpression, transcriptomic profiling, γH2AX immunostaining, colony-formation and nude-mouse xenograft assays

    PMID:28186538

    Open questions at the time
    • Direct chromatin occupancy at Atm/Atrx/Brca2 loci not demonstrated
    • Mechanism linking nucleosome binding to gene repression unknown
    • Loss-of-function phenotype in normal physiology not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HMGN4 nucleosome binding is mechanistically coupled to transcriptional repression of specific tumor suppressors and to DNA damage signaling remains unresolved.
  • No genome-wide binding map
  • No structural basis for target selectivity
  • No identified protein partners or chromatin co-factors

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 2

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HMGN4 (encoded by an intronless gene at chromosome 6p21.3) is a nuclear protein closely related to HMGN2 that localizes to the nucleus in HeLa cells and binds nucleosomes, expanding the HMGN protein family of nucleosome-binding proteins. Western blot with antibody against unique HMGN4 region, transfection of HeLa cells with HMGN4-GFP fusion for nuclear localization, Northern blot for tissue expression DNA and cell biology Medium 11410162
2017 Overexpression of HMGN4 in mouse and human cells alters the cellular transcription profile, downregulates tumor suppressors Atm, Atrx, and Brca2, elevates the DNA damage marker γH2AX, and increases tumorigenicity as measured by colony formation and tumor generation in nude mice; transgenic mice overexpressing HMGN4 in the thyroid develop preneoplastic lesions, establishing HMGN4 as an epigenetic factor that potentiates thyroid oncogenesis. Transgenic mouse overexpression, colony formation assays, nude mouse tumor xenograft, transcriptomic profiling, γH2AX immunostaining, gene expression analysis Carcinogenesis Medium 28186538

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles. Accounts of chemical research 208 30653296
2009 Metal-NHC complexes: a survey of anti-cancer properties. Dalton transactions (Cambridge, England : 2003) 162 20449127
2006 (NHC)Copper(I)-catalyzed [3+2] cycloaddition of azides and mono- or disubstituted alkynes. Chemistry (Weinheim an der Bergstrasse, Germany) 138 16969776
2003 Characterization of a spontaneously immortalized cell line (IOBA-NHC) from normal human conjunctiva. Investigative ophthalmology & visual science 123 14507870
2017 Gold(I) NHC Complexes: Antiproliferative Activity, Cellular Uptake, Inhibition of Mammalian and Bacterial Thioredoxin Reductases, and Gram-Positive Directed Antibacterial Effects. Chemistry (Weinheim an der Bergstrasse, Germany) 121 27865002
2012 Rollover cyclometalation pathway in rhodium catalysis: dramatic NHC effects in the C-H bond functionalization. Journal of the American Chemical Society 91 23013604
2014 A TrxR inhibiting gold(I) NHC complex induces apoptosis through ASK1-p38-MAPK signaling in pancreatic cancer cells. Molecular cancer 86 25253202
2011 NHC gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents. Journal of medicinal chemistry 86 22091836
2020 Photoinduced Single-Electron Transfer as an Enabling Principle in the Radical Borylation of Alkenes with NHC-Borane. Angewandte Chemie (International ed. in English) 74 31849140
2009 Synthesis, structural characterisation and anti-proliferative activity of NHC gold amino acid and peptide conjugates. Dalton transactions (Cambridge, England : 2003) 73 20449149
2015 Gold(I) NHC-based homo- and heterobimetallic complexes: synthesis, characterization and evaluation as potential anticancer agents. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 72 26202908
2012 Imidazol(in)ium hydrogen carbonates as a genuine source of N-heterocyclic carbenes (NHCs): applications to the facile preparation of NHC metal complexes and to NHC-organocatalyzed molecular and macromolecular syntheses. Journal of the American Chemical Society 67 22455795
2017 Characterization of Hydrophilic Gold(I) N-Heterocyclic Carbene (NHC) Complexes as Potent TrxR Inhibitors Using Biochemical and Mass Spectrometric Approaches. Inorganic chemistry 62 29095609
2022 Pt(II)-NHC Complex Induces ROS-ERS-Related DAMP Balance to Harness Immunogenic Cell Death in Hepatocellular Carcinoma. Journal of medicinal chemistry 57 35025488
2011 Gold(I)-NHC complexes of antitumoral diarylimidazoles: structures, cellular uptake routes and anticancer activities. Journal of inorganic biochemistry 52 22112840
2018 On the Mechanism of Gold/NHC Compounds Binding to DNA G-Quadruplexes: Combined Metadynamics and Biophysical Methods. Angewandte Chemie (International ed. in English) 50 29972613
2017 Novel NHC Precursors: Synthesis, Characterization, and Carbonic Anhydrase and Acetylcholinesterase Inhibitory Properties. Archiv der Pharmazie 48 28464340
2008 Comparative study on the cytotoxic effects of benzalkonium chloride on the Wong-Kilbourne derivative of Chang conjunctival and IOBA-NHC cell lines. Molecular vision 48 18334956
2020 Potent Inhibition of Thioredoxin Reductase by the Rh Derivatives of Anticancer M(arene/Cp*)(NHC)Cl2 Complexes. Inorganic chemistry 46 32073260
2020 Facile H/D Exchange at (Hetero)Aromatic Hydrocarbons Catalyzed by a Stable Trans-Dihydride N-Heterocyclic Carbene (NHC) Iron Complex. Journal of the American Chemical Society 45 32902969
2020 [Pd(NHC)(μ-Cl)Cl]2: Versatile and Highly Reactive Complexes for Cross-Coupling Reactions that Avoid Formation of Inactive Pd(I) Off-Cycle Products. iScience 44 32759055
2023 Tumor-Targeting NHC-Au(I) Complex Induces Immunogenic Cell Death in Hepatocellular Carcinoma. Journal of medicinal chemistry 43 36827091
2019 A new rhodium(I) NHC complex inhibits TrxR: In vitro cytotoxicity and in vivo hepatocellular carcinoma suppression. European journal of medicinal chemistry 42 31577978
2020 Halo and Pseudohalo Gold(I)-NHC Complexes Derived from 4,5-Diarylimidazoles with Excellent In Vitro and In Vivo Anticancer Activities Against HCC. Journal of medicinal chemistry 41 32787098
2013 Mechanism and origins of ligand-controlled selectivities in [Ni(NHC)]-catalyzed intramolecular (5 + 2) cycloadditions and homo-ene reactions: a theoretical study. Journal of the American Chemical Society 38 23273283
2011 A study on applications of N-substituted main-chain NHC-palladium polymers as recyclable self-supported catalysts for the Suzuki-Miyaura coupling of aryl chlorides in water. Inorganic chemistry 38 21648445
2012 Pyrazine functionalized Ag(I) and Au(I)-NHC complexes are potential antibacterial agents. Current medicinal chemistry 36 22680631
2020 Photocatalytic C-F Bond Borylation of Polyfluoroarenes with NHC-boranes. Organic letters 34 32052975
2018 Synthesis of new allyl palladium complexes bearing purine-based NHC ligands with antiproliferative and proapoptotic activities on human ovarian cancer cell lines. Dalton transactions (Cambridge, England : 2003) 34 30207339
2015 Pincer-Type Platinum(II) Complexes Containing N-Heterocyclic Carbene (NHC) Ligand: Structures, Photophysical and Anion-Binding Properties, and Anticancer Activities. Chemistry (Weinheim an der Bergstrasse, Germany) 33 25828963
2001 HMGN4, a newly discovered nucleosome-binding protein encoded by an intronless gene. DNA and cell biology 33 11410162
2020 Cytotoxic Ag(I) and Au(I) NHC-carbenes bind DNA and show TrxR inhibition. Journal of inorganic biochemistry 32 31981769
2020 Novel NHC-coordinated ruthenium(II) arene complexes achieve synergistic efficacy as safe and effective anticancer therapeutics. European journal of medicinal chemistry 32 32688202
2008 From large 12-membered macrometallacycles to ionic (NHC)2M+Cl- type complexes of gold and silver by modulation of the N-substituent of amido-functionalized N-heterocyclic carbene (NHC) ligands. Inorganic chemistry 31 18410089
2020 An Artemisinin-Derivative-(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity. Angewandte Chemie (International ed. in English) 30 32304346
2018 Pharmacomodulation on Gold-NHC complexes for anticancer applications - is lipophilicity the key point? European journal of medicinal chemistry 30 30099254
2017 On the binding modes of metal NHC complexes with DNA secondary structures: implications for therapy and imaging. Chemical communications (Cambridge, England) 30 28653066
2020 NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl Halides. Journal of the American Chemical Society 29 32250612
2019 Chemistry, structure, and biological roles of Au-NHC complexes as TrxR inhibitors. Bioorganic chemistry 29 31911299
2015 Human colon cancer targeted pro-apoptotic, anti-metastatic and cytostatic effects of binuclear Silver(I)-N-Heterocyclic carbene (NHC) complexes. European journal of medicinal chemistry 29 26649905
2019 p53-Dependent Anti-Proliferative and Pro-Apoptotic Effects of a Gold(I) N-Heterocyclic Carbene (NHC) Complex in Colorectal Cancer Cells. Frontiers in oncology 28 31231607
2018 A Ruthenium(II) N-Heterocyclic Carbene (NHC) Complex with Naphthalimide Ligand Triggers Apoptosis in Colorectal Cancer Cells via Activating the ROS-p38 MAPK Pathway. International journal of molecular sciences 27 30544880
2012 Chain-growth polymerization of aryl Grignards initiated by a stabilized NHC-Pd precatalyst. Macromolecular rapid communications 27 22488735
2023 SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer. Pharmacological research 26 36933755
2013 Computational study of the hydrodefluorination of fluoroarenes at [Ru(NHC)(PR3)2(CO)(H)2]: predicted scope and regioselectivities. Dalton transactions (Cambridge, England : 2003) 26 23400241
2013 Potential of silver against human colon cancer: (synthesis, characterization and crystal structures of xylyl (Ortho, meta, &Para) linked bis-benzimidazolium salts and Ag(I)-NHC complexes: In vitro anticancer studies). Chemistry Central journal 25 23391345
2020 Coligand role in the NHC nickel catalyzed C-F bond activation: investigations on the insertion of bis(NHC) nickel into the C-F bond of hexafluorobenzene. Chemical science 24 34094350
2022 Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) by Functionalized NHC-Based Polynuclear Catalysts: Scope and Mechanistic Insights. Organometallics 23 35971402
2016 Novel cis-[(NHC)1(NHC)2(L)Cl]platinum(ii) complexes - synthesis, structures, and anticancer activities. Dalton transactions (Cambridge, England : 2003) 23 27603959
2015 Cytotoxic activity and protein binding through an unusual oxidative mechanism by an iridium(I)-NHC complex. Chemical communications (Cambridge, England) 23 25605442
2015 Global Metabonomic and Proteomic Analysis of Human Conjunctival Epithelial Cells (IOBA-NHC) in Response to Hyperosmotic Stress. Journal of proteome research 23 26260330
2016 Luminescent bioactive NHC-metal complexes to bring light into cells. Dalton transactions (Cambridge, England : 2003) 22 26631876
2015 N-heterocyclic carbenes (NHC) with 1,2,4-oxadiazole-substituents related to natural products: synthesis, structure and potential antitumor activity of some corresponding gold(I) and silver(I) complexes. European journal of medicinal chemistry 22 26185007
2022 N-Heterocyclic Carbene (NHC) Silver Complexes as Versatile Chemotherapeutic Agents Targeting Human Topoisomerases and Actin. ChemMedChem 21 35904129
2023 New Insights into the Behavior of NHC-Gold Complexes in Cancer Cells. Pharmaceutics 20 36839788
2023 Divergent Acyl and Decarbonylative Liebeskind-Srogl Cross-Coupling of Thioesters by Cu-Cofactor and Pd-NHC (NHC = N-Heterocyclic Carbene) Catalysis. ACS catalysis 20 38037656
2014 Water-soluble NHC-Cu catalysts: applications in click chemistry, bioconjugation and mechanistic analysis. Organic & biomolecular chemistry 20 25251642
2020 Novel Anticancer NHC*-Gold(I) Complexes Inspired by Lepidiline A. Molecules (Basel, Switzerland) 19 32751607
2020 The anticancer activity of an air-stable Pd(I)-NHC (NHC = N-heterocyclic carbene) dimer. Chemical communications (Cambridge, England) 19 32926011
2014 DFT study on the reaction mechanisms and stereoselectivities of NHC-catalyzed [2 + 2] cycloaddition between arylalkylketenes and electron-deficient benzaldehydes. Organic & biomolecular chemistry 19 24940721
2022 Investigations of the reactivity, stability and biological activity of halido (NHC)gold(I) complexes. Dalton transactions (Cambridge, England : 2003) 18 34989741
2020 NHC-stabilized Parent Arsanylalanes and -gallanes. Angewandte Chemie (International ed. in English) 18 33197127
2019 Expanding the biological utility of bis-NHC gold(i) complexes through post synthetic carbamate conjugation. Chemical communications (Cambridge, England) 18 31429450
2019 Synthesis, characterization, and biological studies of multidentate gold(i) and gold(iii) NHC complexes. Dalton transactions (Cambridge, England : 2003) 18 31657405
2015 Stereo- and Chemodivergent NHC-Promoted Functionalisation of Arylalkylketenes with Chloral. Chemistry (Weinheim an der Bergstrasse, Germany) 18 26406613
2024 Mechanism and Origin of Stereoselectivity for the NHC-Catalyzed Desymmetrization Reaction for the Synthesis of Axially Chiral Biaryl Aldehydes. The Journal of organic chemistry 17 38359780
2022 Access to Sulfoxides under NHC/Photocatalysis via a Radical Pathway. Organic letters 17 35262358
2018 Synthesis and Cytotoxicity Studies of Novel NHC*-Gold(I) Complexes Derived from Lepidiline A. Molecules (Basel, Switzerland) 17 30110951
2018 NHC-Catalyzed Dual Stetter Reaction: A Mild Cascade Annulation for the Syntheses of Naphthoquinones, Isoflavanones, and Sugar-Based Chiral Analogues. The Journal of organic chemistry 17 30562016
2016 Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting. Bioconjugate chemistry 17 27115175
2020 Antiproliferative Activity of Functionalized Histidine-derived Au(I) bis-NHC Complexes for Bioconjugation. Chemistry, an Asian journal 16 32592289
2020 On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules. Molecules (Basel, Switzerland) 16 33233711
2017 Metal NHC Complexes with Naphthalimide Ligands as DNA-Interacting Antiproliferative Agents. ChemMedChem 16 27997743
2017 Aptamer-mediated selective delivery of a cytotoxic cationic NHC-Au(i) complex to cancer cells. Dalton transactions (Cambridge, England : 2003) 16 29192701
2023 Design, synthesis, characterization, crystal structure, in silico studies, and inhibitory properties of the PEPPSI type Pd(II)NHC complexes bearing chloro/fluorobenzyl group. Bioorganic chemistry 14 37030104
2021 Synthesis, characterization, antimicrobial and antibiofilm activity, and molecular docking analysis of NHC precursors and their Ag-NHC complexes. Dalton transactions (Cambridge, England : 2003) 14 34647935
2020 NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice. Communications biology 14 31909202
1978 Production and characterization of antisera against three individual NHC proteins; a case of a generally distributed NHC protein. Chromosoma 14 357114
2023 NHC-Catalyzed Regioselective Intramolecular Radical Cyclization Reaction for the Synthesis of Benzazepine Derivatives. Organic letters 13 37550857
2022 The effects of two gold-N-heterocyclic carbene (NHC) complexes in ovarian cancer cells: a redox proteomic study. Cancer chemotherapy and pharmacology 13 35543764
2022 Facile Benzylic Alkylation of Arenes with Alcohols by Catalysis with Spirocyclic NHC IrIII Pincer Complex. Angewandte Chemie (International ed. in English) 13 35866449
2020 Enantioselective Synthesis of Tricyclic β-Lactones by NHC-Catalyzed Desymmetrization of Cyclic 1,3-Diketones. Organic letters 13 32609522
2020 A Combined Spectroscopic and Protein Crystallography Study Reveals Protein Interactions of RhI(NHC) Complexes at the Molecular Level. Inorganic chemistry 13 33180473
2024 A New Class of Gold(I) NHC Complexes with Proapoptotic and Resensitizing Properties towards Multidrug Resistant Leukemia Cells Overexpressing BCL-2. Journal of medicinal chemistry 12 39196554
2022 Ir and NHC Dual Chiral Synergetic Catalysis: Mechanism and Stereoselectivity in γ-Butyrolactone Formation. Journal of the American Chemical Society 12 36006026
2020 Mechanisms underlying the cytotoxic activity of syn/anti-isomers of dinuclear Au(I) NHC complexes. European journal of medicinal chemistry 12 32693297
2018 Fluorescent functionalised naphthalimides and their Au(i)-NHC complexes for potential use in cellular bioimaging. Dalton transactions (Cambridge, England : 2003) 12 30566132
2020 Solving the challenging synthesis of highly cytotoxic silver complexes bearing sterically hindered NHC ligands with mechanochemistry. Dalton transactions (Cambridge, England : 2003) 11 32856673
2017 NHC-Cu(I)-Catalyzed Friedländer-Type Annulation of Fluorinated o-Aminophenones with Alkynes on Water: Competitive Base-Catalyzed Dibenzo[b,f][1,5]diazocine Formation. The Journal of organic chemistry 11 28686022
2016 A DFT study on NHC-catalyzed intramolecular aldehyde-ketone crossed-benzoin reaction: mechanism, regioselectivity, stereoselectivity, and role of NHC. Organic & biomolecular chemistry 11 27306484
2023 Biological Activities of Ruthenium NHC Complexes: An Update. Antibiotics (Basel, Switzerland) 10 36830276
2023 Single-Crystal to Single-Crystal Transformations: Stepwise CO2 Insertions into Bridging Hydrides of [(NHC)CuH]2 Complexes. Angewandte Chemie (International ed. in English) 10 37221959
2022 Reactivity and Enantioselectivity in NHC Organocatalysis Provide Evidence for the Complex Role of Modifications at the Secondary Sphere. Journal of the American Chemical Society 10 36535039
2021 Transamidation of Amides and Amidation of Esters by Selective N-C(O)/O-C(O) Cleavage Mediated by Air- and Moisture-Stable Half-Sandwich Nickel(II)-NHC Complexes. Molecules (Basel, Switzerland) 10 33401664
2021 Design, scope and mechanism of highly active and selective chiral NHC-iridium catalysts for the intramolecular hydroamination of a variety of unactivated aminoalkenes. Chemical science 10 34163649
2021 Ru-NHC-Catalyzed Asymmetric Hydrogenation of 2-Quinolones to Chiral 3,4-Dihydro-2-Quinolones. Angewandte Chemie (International ed. in English) 10 34460127
2020 Unveiling the Chemo- and Stereoselectivities of NHC-Catalyzed Reactions of an Aliphatic Ester with Aminochalcone. The Journal of organic chemistry 10 32529828
2017 Elevated HMGN4 expression potentiates thyroid tumorigenesis. Carcinogenesis 10 28186538
2015 Cytotoxic potency of self-assembled Ruthenium(II)-NHC complexes with pincer type 2, 6-bis(N-methylimidazolylidene/benzimidazolylidene)pyrazine ligands. Journal of cancer research and therapeutics 10 25879346
2015 4-Alkylated Silver-N-Heterocyclic Carbene (NHC) Complexes with Cytotoxic Effects in Leukemia Cells. ChemMedChem 10 26250720

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