Affinage

HMGA1

High mobility group protein HMG-I/HMG-Y · UniProt P17096

Length
107 aa
Mass
11.7 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HMGA1 is a non-histone architectural chromatin protein that orchestrates gene expression programs controlling insulin signaling, cell cycle progression, hematopoietic differentiation, genomic stability, lipid metabolism, and ferroptosis resistance. It binds AT-rich DNA via conserved AT-hook motifs whose affinity is modulated by Cdc2 and ATM kinase phosphorylation, and it cross-links separate DNA molecules to reorganize chromatin architecture, forming enhanceosome complexes that recruit transcription factors (C/EBPβ, FOXM1, ATF4, SREBP1) and active histone marks (H3K4me3, H3K27Ac) to target promoters including INSR, GATA2, FGF19, FASN, SLC7A11, COX-2, VEGFA, and specific miRNA clusters (PMID:11406267, PMID:15924147, PMID:35286385, PMID:36919699, PMID:38383528, PMID:21596776). Beyond its nuclear functions, HMGA1 translocates to mitochondria during S/G2 phase where it binds the D-loop to regulate mtDNA transcription and copy number, interacts with 7SK snRNA to couple transcriptional initiation with P-TEFb-dependent elongation, and is secreted extracellularly where it ligates RAGE to activate ERK signaling (PMID:17045586, PMID:21087998, PMID:24623795, PMID:30135148). Loss of HMGA1 expression markedly reduces insulin receptor levels and causes a type 2 diabetes phenotype in mice and humans (PMID:15924147).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 High

    Establishing that HMGA1's DNA-binding activity is dynamically regulated through the cell cycle resolved how this architectural factor could be switched on and off: Cdc2 kinase phosphorylates the AT-hook domains, reducing DNA-binding affinity.

    Evidence In vitro kinase assay with cell cycle analysis

    PMID:9552376

    Open questions at the time
    • Phosphorylation-dependent changes in specific target gene expression not mapped
    • In vivo cell-cycle dynamics of HMGA1 phosphorylation not directly measured
  2. 2001 High

    Defining the structural basis of HMGA1 function — AT-hook motif-mediated minor groove binding and conformational flexibility enabling stereospecific enhanceosome assembly — established the foundational model for how a non-histone protein organizes transcription factor complexes on promoters.

    Evidence Biochemical DNA binding assays and structural analysis of AT-hook motifs

    PMID:11406267

    Open questions at the time
    • No high-resolution co-crystal structure of full-length HMGA1 on a natural enhanceosome
    • Stoichiometry of AT-hook engagement at specific enhanceosomes undefined
  3. 2001 High

    Demonstrating that HMGA1b overexpression deregulates the cell cycle and induces caspase-3-dependent apoptosis — dependent on the third AT-hook and K60 acetylation — revealed that HMGA1 dosage is critical and that post-translational modifications specify distinct functional outcomes.

    Evidence Stable overexpression with site-directed mutagenesis, cell cycle and caspase assays in rat thyroid cells

    PMID:11389094

    Open questions at the time
    • Acetyltransferase responsible for K60 acetylation not identified
    • Relevance of apoptosis induction to physiological HMGA1 expression levels unclear
  4. 2003 High

    Two discoveries established HMGA1 as a lineage-determining and oncogenic transcription organizer: it is required for KiMSV-driven neoplastic transformation (through AP-1 activity) and controls lympho-hematopoietic differentiation from ES cells via GATA-1 transactivation.

    Evidence Antisense suppression with transformation/xenograft assays; Hmga1-null ES cell differentiation with GATA-1 rescue

    PMID:12082527 PMID:12824305

    Open questions at the time
    • Genome-wide chromatin occupancy in hematopoietic progenitors not mapped
    • Direct versus indirect AP-1 regulation not distinguished
  5. 2005 High

    Linking HMGA1 to insulin receptor transcription and type 2 diabetes in mice and humans demonstrated that this architectural factor is essential for metabolic homeostasis, not only transformation.

    Evidence Hmga1 knockout mice, HMGA1 transfection rescue in patient cells, insulin binding assays

    PMID:15924147

    Open questions at the time
    • Complete spectrum of HMGA1 loss-of-function variants in human diabetes cohorts not defined
    • Tissue-specific conditional KO phenotypes not fully characterized at this time
  6. 2006 High

    Discovery that HMGA1 translocates to mitochondria in late S/G2 phase and directly binds the D-loop to alter mtDNA transcription, copy number, and ROS levels revealed a non-nuclear function, extending its role beyond chromatin architecture.

    Evidence Inducible HA-HMGA1 in MCF-7 cells with mitochondrial fractionation, qRT-PCR, flow cytometry, ATP measurement

    PMID:17045586 PMID:19687300

    Open questions at the time
    • Mitochondrial import mechanism for HMGA1 not identified
    • Whether mtDNA binding uses the same AT-hook contacts as nuclear DNA not resolved
  7. 2007 High

    Two studies revealed how HMGA1 drives cell cycle progression through distinct mechanisms: it forms a C/EBPβ complex at the IR promoter to control cyclin D1 translation via 4E-BP1, and it binds RB's small pocket to displace HDAC1 and de-repress E2F/cyclin E transcription.

    Evidence Co-IP, reporter assays, cell cycle analysis in pancreatic cancer cells; RB competition assay under serum starvation

    PMID:17510394 PMID:17877762

    Open questions at the time
    • Whether RB-HMGA1 interaction occurs on chromatin or in the nucleoplasm not determined
    • Relative contributions of IR-dependent versus RB-dependent cell cycle effects not quantified
  8. 2008 High

    Identification of HMGA1 as an ATM kinase substrate that co-localizes with activated ATM after ionizing radiation connected HMGA1 to the DNA damage response, suggesting its phosphorylation state modulates radiation sensitivity.

    Evidence In vitro kinase assay with SQ motif identification, confocal co-localization, clonogenic survival assay

    PMID:18783938

    Open questions at the time
    • Functional consequence of ATM-mediated HMGA1 phosphorylation on specific repair pathways not characterized
    • Whether HMGA1 recruits repair factors to damage sites not tested
  9. 2009 High

    Discovery that HMGA1 binds upstream regulatory regions of specific miRNAs (miR-196a-2, miR-101b, miR-331, miR-29a) and thereby controls HMGA2 levels expanded the gene-regulatory repertoire of HMGA1 to non-coding RNA networks.

    Evidence miRNA microarray in Hmga1-null MEFs, ChIP for HMGA1 at miRNA regulatory regions

    PMID:19169275

    Open questions at the time
    • Full scope of HMGA1-regulated miRNAs genome-wide not determined
    • Direct versus enhanceosome-mediated miRNA promoter regulation not distinguished
  10. 2010 High

    The finding that 7SK snRNA directly binds HMGA1's first AT-hook (competing with DNA) and regulates >1500 HMGA1 target genes introduced an RNA-based regulatory layer controlling HMGA1 chromatin occupancy.

    Evidence RNA-protein binding assay with domain mapping, transcriptome profiling

    PMID:21087998

    Open questions at the time
    • Whether 7SK-HMGA1 interaction is dynamically regulated during the cell cycle not known
    • Structural basis of 7SK loop 2 recognition by AT-hook not resolved
  11. 2011 High

    Demonstrating that HMGA1a cross-links two distinct DNA molecules via a novel cross-linking domain — causing chromatin aggregation and DNA looping — established HMGA1 as an active chromatin organizer beyond simple enhanceosome scaffolding.

    Evidence DNA cross-linking assay, dSTORM super-resolution microscopy, electron microscopy, point mutagenesis

    PMID:21596776

    Open questions at the time
    • Genome-wide identification of DNA cross-linking sites not performed
    • Physiological contexts requiring inter-molecular DNA bridging not defined
  12. 2011 Medium

    Identification of ternary 7SK/HMGA1/P-TEFb complexes that cooperate at specific gene promoters provided a mechanism coupling HMGA1-mediated transcriptional initiation to P-TEFb-dependent elongation.

    Evidence 7SK RNA immunoprecipitation detecting simultaneous HMGA1/P-TEFb, transcriptome profiling with dominant-negative Cdk9

    PMID:21957495

    Open questions at the time
    • Genome-wide mapping of sites where HMGA1 and P-TEFb co-occupy promoters not done
    • Mechanism distinguishing P-TEFb-dependent from P-TEFb-independent HMGA1 targets unclear
  13. 2014 High

    Showing that HMGA1 recruits the inactive 7SK/P-TEFb/CTIP2 complex to promoters — and that HMGA1 and CTIP2 synergistically repress transcription (including HIV-1) — clarified that HMGA1 can function as both activator and repressor depending on the cofactor complex assembled.

    Evidence ChIP for 7SK/P-TEFb/CTIP2 recruitment ± HMGA1 knockdown, HIV-1 promoter reporter

    PMID:24623795

    Open questions at the time
    • How HMGA1 switches between activating and repressive modes at specific loci not mechanistically resolved
    • In vivo relevance for HIV-1 latency not established
  14. 2015 High

    Linking HMGA1 to spindle assembly checkpoint gene transcription (Ttk, Mad2l1, Bub1, Bub1b) explained how HMGA1 overexpression contributes to chromosome instability — a hallmark of cancer — through direct promoter binding.

    Evidence ChIP at SAC gene promoters, HMGA1 depletion with live-cell imaging of mitotic defects, clinical correlation in colon carcinomas

    PMID:26009897

    Open questions at the time
    • Whether SAC gene regulation is dose-dependent on HMGA1 levels not quantified
    • Interaction with other mitotic regulators at SAC promoters not explored
  15. 2018 High

    Discovery that extracellular HMGA1 acts as a RAGE ligand activating ERK signaling to promote migration/invasion revealed a non-cell-autonomous signaling function, fundamentally expanding the protein's functional repertoire beyond chromatin.

    Evidence HMGA1-blocking antibody, pERK signaling assays, migration/invasion assays, xenograft models in triple-negative breast cancer

    PMID:30135148

    Open questions at the time
    • Secretion mechanism for HMGA1 not identified
    • Whether eHMGA1-RAGE signaling operates in normal physiology not tested
  16. 2022 High

    ChIP-seq in myeloproliferative neoplasm models showed HMGA1 directly opens chromatin at the GATA2 +9.5 enhancer region and recruits H3K4me3/H3K27Ac, with GATA2 silencing recapitulating HMGA1 loss, establishing a chromatin-accessibility mechanism for lineage-specific transcriptional control.

    Evidence CRISPR/shRNA/genetic deletion, ChIP-seq for HMGA1 and histone marks, epistasis via GATA2 silencing in JAK2V617F MPN models

    PMID:35286385

    Open questions at the time
    • Whether HMGA1 directly recruits histone-modifying enzymes or acts passively via chromatin opening not distinguished
    • Applicability to normal hematopoiesis versus MPN-specific context not resolved
  17. 2023 High

    Demonstrating that HMGA1 recruits active histone marks to the FGF19 locus and that FGF19/FGFR4 signaling mediates HMGA1-driven pancreatic tumor progression identified a paracrine effector axis linking HMGA1 chromatin remodeling to desmoplastic stroma formation.

    Evidence ChIP for HMGA1 and histone marks at FGF19, FGF19 silencing, FGFR4 pharmacological inhibition, KPC mouse model

    PMID:36919699

    Open questions at the time
    • Whether HMGA1-FGF19 axis operates in normal pancreatic tissue not tested
    • Mechanism by which HMGA1 recruits histone-modifying enzymes not identified
  18. 2024 High

    Two 2024 studies expanded HMGA1's metabolic and stress-response roles: conditional intestinal KO/knock-in mice showed HMGA1 cooperates with SREBP1 to activate FASN and lipid synthesis in colorectal cancer, while ChIP demonstrated HMGA1 facilitates ATF4 binding at the SLC7A11 promoter to suppress ferroptosis and confer cisplatin resistance.

    Evidence Conditional Hmga1 KO/KI mouse models with FASN reporter assays; ChIP for ATF4 at SLC7A11 ± HMGA1 with syngeneic allograft and GEM models

    PMID:38383528 PMID:39548107

    Open questions at the time
    • Whether lipid synthesis and ferroptosis resistance are interconnected downstream of HMGA1 not explored
    • Structural basis for HMGA1 cooperation with SREBP1 versus ATF4 at distinct promoters unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the mechanism of HMGA1 mitochondrial import and extracellular secretion; whether HMGA1 directly recruits histone-modifying enzymes or passively enables their access through chromatin opening; the structural basis of context-dependent activator-versus-repressor switching; and the full genome-wide map of HMGA1-mediated DNA cross-linking sites that reorganize three-dimensional chromatin architecture.
  • Mitochondrial targeting signal or import machinery not identified
  • No high-resolution structure of HMGA1 in an enhanceosome complex
  • Genome-wide 3D chromatin reorganization by HMGA1 cross-linking not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 13 GO:0003677 DNA binding 11 GO:0003723 RNA binding 3 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005634 nucleus 7 GO:0005694 chromosome 3 GO:0005739 mitochondrion 2 GO:0005576 extracellular region 1
Pathway
R-HSA-74160 Gene expression (Transcription) 15 R-HSA-1643685 Disease 8 R-HSA-1640170 Cell Cycle 7 R-HSA-4839726 Chromatin organization 5 R-HSA-162582 Signal Transduction 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AGERATF4CD274CEBPBFOXM1HSPA9RB1SREBF1
Complex memberships
7SK/P-TEFb snRNPC/EBPβ/HMGA1 enhanceosomeCTIP2/7SK/P-TEFb repressive complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HMGA1 proteins bind to the narrow minor groove of AT-rich DNA sequences via multiple conserved 'AT hook' peptide motifs, and assume distinct conformations upon binding to DNA or other proteins, enabling formation of stereospecific 'enhanceosome' complexes on gene promoter/enhancer regions that regulate transcription. Biochemical characterization, DNA binding assays, structural analysis of AT-hook motifs Biochimica et biophysica acta High 11406267
1995 HMGA1 proteins are substrates for cell cycle-regulated Cdc2 kinase, which phosphorylates the DNA-binding AT-hook domains and decreases substrate binding affinity, providing a reversible mechanism for cell cycle-dependent regulation of HMGA1 function. In vitro kinase assay, cell cycle analysis Progress in cell cycle research High 9552376
2005 HMGA1 is required for normal transcription of the insulin receptor (INSR) gene; loss of HMGA1 expression markedly decreases INSR expression in major insulin target tissues, impairs insulin signaling, reduces insulin secretion, and causes a type 2 diabetes phenotype in mice and humans. Hmga1 knockout mice, gene rescue by HMGA1 transfection in patient cells, insulin binding assays Nature medicine High 15924147
2001 HMGA1b protein overexpression in normal rat thyroid cells deregulates the cell cycle (earlier S-phase entry, delayed G2-M transition) and induces apoptosis via caspase-3 activation; the third AT-hook domain and acetylation site K60 are required for apoptosis induction. Stable overexpression, cell cycle analysis, caspase assays, site-directed mutagenesis Cancer research High 11389094
2003 HMGA1 is required for neoplastic transformation of rat thyroid cells by Kirsten murine sarcoma virus; antisense suppression of HMGA1 prevents malignant phenotype (soft agar growth, tumor formation in athymic mice) and blocks AP-1 transcriptional activity induction. Antisense construct transfection, retroviral transformation assay, soft agar colony formation, xenograft in athymic mice, AP-1 reporter assay Oncogene High 12082527
2003 HMGA1 controls embryonic stem cell lympho-hematopoietic differentiation; Hmga1-null ES cells show skewed T/B cell balance and altered monocyte/megakaryocyte/erythrocyte lineages; HMGA1 directly controls GATA-1 transcription as part of this mechanism. Hmga1-null ES cell differentiation assays, cytokine expression analysis, gene rescue experiments, GATA-1 transcription analysis FASEB journal High 12824305
2006 HMGA1 directly binds to mitochondrial DNA (mtDNA) at the D-loop control region and translocates from nucleus to mitochondria during late S/G2 phase; overexpression of HMGA1 reduces mtDNA levels and mitochondrial mass, alters mitochondrial transcription (upregulates heavy and light strand gene transcripts ~3-fold), reduces cellular ATP, increases reactive oxygen species, and increases mitochondrial membrane potential. Transgenic MCF-7 cells with inducible HA-HMGA1, quantitative RT-PCR for mtDNA transcripts, flow cytometry, ATP measurement, mitochondrial fractionation Experimental cell research High 17045586
2009 Elevated HMGA1 levels reduce mtDNA copy number, decrease mitochondrial mass, increase cellular reactive oxygen species, and impair repair efficiency of oxidatively damaged mtDNA; these effects are reversible and parallel changes in HMGA1 concentration. Inducible HMGA1 expression in MCF-7 cells, turn-ON/turn-OFF time-course, flow cytometry, oxidative DNA damage repair assays Molecular and cellular biology High 19687300
2007 HMGA1 controls transcription of the insulin receptor (IR) gene via a C/EBPβ/HMGA1 complex at the IR promoter; this drives cyclin D1 expression at the translational level through the eIF4E repressor 4E-BP1 downstream of IR signaling, promoting G1-phase progression in pancreatic cancer cells. siRNA knockdown, reporter assays, co-immunoprecipitation of C/EBPβ/HMGA1 complex, cell cycle analysis, western blot for 4E-BP1/cyclin D1 Cancer research High 17510394
2007 HMGA1 binds the small pocket domain of retinoblastoma protein (RB) and competes with HDAC1 for this interaction; HMGA1 overexpression abolishes RB-mediated repression of E2F-driven transcription from the cyclin E promoter and abrogates G0 arrest under serum starvation. Co-immunoprecipitation, luciferase reporter assay (cyclin E promoter), cell cycle analysis under serum starvation Cancer science High 17877762
2008 HMGA1 is a novel substrate of ATM kinase; an SQ motif on HMGA1 is phosphorylated by ATM in vitro and in vivo; HMGA1 co-localizes with activated ATM (ATM S1981p) in the nucleus after ionizing radiation; HMGA1 overexpression decreases clonogenic survival after irradiation. In vitro kinase assay, co-localization by confocal microscopy, clonogenic survival assay after ionizing radiation European journal of cancer High 18783938
2010 7SK small nuclear RNA directly interacts with HMGA1 through loop 2 of 7SK RNA binding the first AT-hook motif, competing with DNA binding to the same domain; this interaction regulates over 1500 HMGA1 target genes in a P-TEFb-independent manner and affects HMGA1-dependent cell differentiation and proliferation. RNA-protein binding assay, transcriptome profiling, domain mapping of 7SK-HMGA1 interaction Nucleic acids research High 21087998
2011 7SK RNA establishes gene-specific cooperativity between HMGA1 and P-TEFb; 7SK RNA complexes containing both HMGA1 and P-TEFb simultaneously were identified; at select target genes, HMGA1 and P-TEFb cooperate in transcriptional activation. Transcriptome profiling, dominant-negative Cdk9 inhibition, 7SK RNA immunoprecipitation for simultaneous HMGA1/P-TEFb complex RNA biology Medium 21957495
2011 HMGA1a can directly cross-link two distinct DNA molecules simultaneously; this is mediated by a novel DNA cross-linking domain identified by point mutagenesis; HMGA1 overexpression in cells leads to chromatin aggregation, and HMGA1 creates DNA loops and supercoils in linearized DNA in vitro. DNA cross-linking assay, dSTORM super-resolution microscopy, electron microscopy, site-directed mutagenesis Nucleic acids research High 21596776
2012 HMGA1 is a downstream nuclear target of insulin receptor signaling; activation of the insulin receptor by insulin affects HMGA1 protein phosphorylation (reducing DNA-binding affinity and transcriptional activation), establishing HMGA1 as a nuclear mediator of insulin action. Western blot for HMGA1 phosphorylation, DNA binding assays, transcriptional reporter assays after insulin treatment Scientific reports Medium 22355763
2012 HMGA1 directly binds to the COX-2 promoter at an AT-rich region in pancreatic cancer cells and induces COX-2 expression; knockdown of HMGA1 represses COX-2; HMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent growth. Chromatin immunoprecipitation (ChIP) in three pancreatic cancer cell lines, HMGA1 knockdown, migration/invasion assays, soft agar colony formation Pancreatology High 22898640
2012 HMGA1 binds to the promoter of miR-137 in colorectal cancer cells and activates its transcription, thereby reducing FMNL2 expression and inhibiting PI3K/Akt and MAPK signaling. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, HMGA1 knockdown/overexpression, in vitro invasion and in vivo metastasis assays Gastroenterology High 23201162
2014 HMGA1 recruits the inactive 7SK/P-TEFb snRNP complex to cellular gene promoters and the HIV-1 promoter; ChIP shows significant loss of CTIP2/7SK/P-TEFb snRNP recruitment upon HMGA1 knockdown; HMGA1 and CTIP2 synergistically repress P-TEFb-dependent gene expression. Chromatin immunoprecipitation (ChIP), RNA interference (dual CTIP2/HMGA1 knockdown), HIV-1 promoter reporter assay Nucleic acids research High 24623795
2013 HMGA1 directly binds to the HIV-1 TAR RNA element through its AT-hook domain; 7SK RNA competes with TAR for HMGA1 binding; HMGA1 competes with Tat for TAR binding and negatively regulates HIV-1 promoter activity in a TAR-dependent manner. RNA-protein binding assays, competition assays, HIV-1 promoter-luciferase reporter in presence/absence of Tat, HMGA1 knockdown RNA biology High 23392246
2009 HMGA1 proteins regulate expression of specific microRNAs (miR-196a-2, miR-101b, miR-331, miR-29a) by directly binding their upstream regulatory regions; HMGA1 proteins can downregulate HMGA2 expression via regulation of miR-196a-2. miRNA microarray in Hmga1-null MEFs, ChIP assay for HMGA1 binding to miRNA upstream regions, RT-PCR validation Oncogene High 19169275
2015 HMGA1 promotes cell cycle progression through cyclin E2 (CCNE2), which activates YAP nuclear localization and activity by modulating MST1/2 and LATS1/2 kinases of the Hippo pathway; this HMGA1-CCNE2-YAP axis regulates motility and invasiveness in basal-like breast cancer cells. siRNA knockdown, CDK inhibitor treatment, YAP localization assay, Hippo pathway kinase dependency experiments Oncotarget Medium 26265440
2015 HMGA1 activates stemness genes and key migration-associated genes linked to Wnt/β-catenin, Notch, and Pin1/mutant p53 signalling pathways; HMGA1 knockdown induces mesenchymal-to-epithelial transition and reduces self-renewal, migration, invasion and metastasis in basal-like breast cancer. shRNA knockdown, in vitro migration/invasion assays, in vivo metastasis models, pathway reporter assays Oncotarget Medium 23945276
2016 HMGA1 modifies chromatin architecture at the Sox2 promoter to regulate Sox2 expression, functioning as a downstream effector of the miR-296-5p pathway; this HMGA1:Sox2 axis maintains glioblastoma stem cell self-renewal and tumor propagation. miR-296-5p overexpression, HMGA1 knockdown, Sox2 promoter chromatin analysis, glioblastoma sphere formation assays, xenograft in vivo Oncogene Medium 26898758
2017 HMGA1 binds to the FoxO1 gene promoter and activates FoxO1 transcription; forced HMGA1 expression in Hmga1-null hepatocytes and patient-derived lymphoblasts restores FoxO1 mRNA and protein levels. Reporter gene assay, ChIP for HMGA1 binding to FoxO1 promoter, Western blot/qRT-PCR in KO hepatocytes and patient lymphoblasts Endocrine High 29052178
2017 G9a/EHMT2 histone methyltransferase regulates HMGA1 expression; G9a knockdown downregulates HMGA1 and impairs insulin receptor expression and insulin signaling; HMGA1 overexpression normalizes impaired insulin signaling in G9a-depleted cells. siRNA knockdown, overexpression rescue, Western blot, db/db mouse model with G9a restoration Biochimica et biophysica acta. Molecular basis of disease Medium 29101051
2015 HMGA1 deregulation induces chromosome instability by transcriptionally activating spindle assembly checkpoint (SAC) genes Ttk, Mad2l1, Bub1, and Bub1b through direct binding to their promoter regions; HMGA1 depletion causes mitotic defects including unaligned chromosomes, reduced prometaphase time, and increased cytokinesis failure. ChIP for HMGA1 at SAC gene promoters, HMGA1 depletion, live-cell microscopy for mitotic defects, correlation in human colon carcinomas Oncotarget High 26009897
2018 Extracellular HMGA1 (eHMGA1) acts as a ligand for the RAGE receptor in triple-negative breast cancer; eHMGA1 binding to RAGE induces pERK signaling, increasing migration and invasion; blocking eHMGA1 with antibodies impairs migration and invasion in vitro. HMGA1-blocking antibody treatment, signaling assays (pERK), migration/invasion assays, fluorescence microscopy for subcellular localization, xenograft models Clinical cancer research High 30135148
2019 HMGA1 directly interacts with FOXM1 protein, stabilizes it in the nucleus, and increases its transcriptional activity on common target genes including VEGFA; this cooperative HMGA1-FOXM1 axis drives breast cancer angiogenesis. Co-immunoprecipitation, protein stability assays, luciferase assay on VEGFA promoter, tube formation assay, zebrafish xenograft in vivo model Journal of experimental & clinical cancer research High 31311575
2019 PD-L1 directly interacts with HMGA1 protein and upregulates its expression; HMGA1 upregulation by PD-L1 activates PI3K/Akt and MEK/ERK pathways to promote colorectal cancer stem cell expansion; HMGA1 downregulation rescues PD-L1-induced cancer stem cell phenotypes. Co-immunoprecipitation, HMGA1 knockdown rescue experiments, PI3K/Akt and MEK/ERK pathway analysis, tumorsphere formation assays Cancer letters Medium 30776481
2022 HMGA1 binds to a conserved ATTGG site within enhancer II/core promoter of HBV cccDNA and recruits transcription factors FOXO3α and PGC1α to upregulate viral gene expression and genome replication; HBV X protein (HBx) interacts with SP1 to activate HMGA1 promoter, creating a positive feedback loop. ChIP assay, promoter reporter assays, RNA interference in mouse HBV persistence model, co-immunoprecipitation of HBx-SP1 Nucleic acids research High 35137191
2022 HMGA1 depletion (via CRISPR, shRNA, or genetic deletion) in JAK2V617F MPN models disrupts proliferation and leukemic engraftment; HMGA1 directly transactivates GATA2 through sequences near the developmental +9.5 enhancer by increasing chromatin accessibility and recruiting active histone marks (H3K4me3, H3K27Ac); silencing GATA2 recapitulates HMGA1 depletion phenotypes. CRISPR/Cas9, shRNA, genetic deletion, RNA-seq, ChIP-seq for HMGA1 occupancy and histone marks, epistasis via GATA2 silencing and re-expression Blood High 35286385
2023 HMGA1 directly induces FGF19 expression by recruiting active histone marks (H3K4me3, H3K27Ac) to the FGF19 gene locus, increasing FGF19 protein secretion; FGF19 acts as an effector of HMGA1 driving pancreatic tumor progression and desmoplastic stroma formation through FGFR4. RNA-seq, ChIP for HMGA1 and histone marks at FGF19 locus, FGF19 gene silencing, FGFR4 inhibitor (BLU9931), KPC mouse model and subcutaneous/orthotopic xenograft models The Journal of clinical investigation High 36919699
2024 HMGA1 promotes colorectal cancer progression by increasing lipid synthesis; mechanistically, HMGA1 increases transcriptional activity of SREBP1 on the FASN promoter, leading to elevated fatty acid synthase expression and increased lipid accumulation in intestinal epithelial cells. Conditional KO (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mouse models, FASN promoter reporter assays, pharmacological FASN inhibition by orlistat Nature communications High 39548107
2024 NAT10 promotes HMGA1 mRNA stability through N4-acetylcytidine (ac4C) modification of the HMGA1 mRNA, thereby enhancing HMGA1 protein levels and promoting cell cycle progression and proliferation in prostate cancer. NAT10 overexpression/knockdown, ac4C modification assay, mRNA stability assay, Western blot Advanced science Medium 38922788
2021 GRP75 directly binds HMGA1 protein and inhibits its ubiquitination-mediated degradation, thereby stabilizing HMGA1 protein levels in lung adenocarcinoma; the GRP75/HMGA1 axis activates JNK/c-JUN signaling to promote tumor growth and metastasis. Co-immunoprecipitation, ubiquitination assay, mRNA-sequencing for downstream pathways, overexpression and knockdown in vitro and in vivo Thoracic cancer Medium 33755320
2024 HMGA1 promotes SLC7A11 transcription by acting as a chromatin remodeling factor that facilitates binding of activating transcription factor 4 (ATF4) to the SLC7A11 promoter; this maintains intracellular glutathione homeostasis, suppresses ferroptosis, and drives cisplatin resistance in esophageal squamous cell carcinoma. Transcriptome analysis, ChIP for ATF4 at SLC7A11 promoter in presence/absence of HMGA1, HMGA1 KO in syngeneic allograft and genetically engineered mouse models, ferroptosis assays (MDA measurement) Cell death & disease High 38383528
2016 HMGA1 variants that impair HMGA1 protein expression reduce VEGFA expression and protect against proliferative diabetic retinopathy; mechanistically, HMGA1 normally promotes VEGFA gene expression, and reduced HMGA1 function leads to decreased neovascularization. Case-control genetic study, functional HMGA1 reporter assays, VEGFA expression analysis in patient-derived cells Scientific reports Medium 27991577
2019 HMGA1 accelerates G1/S phase transition in cervical cancer by regulating cyclin D1 and cyclin E1 expression; HMGA1 transcriptionally activates the miR-221/222 cluster, which targets TIMP3 3'UTR, leading to increased MMP2/MMP9 activity and promoting migration/invasion. HMGA1 overexpression/knockdown, cell cycle analysis, luciferase reporter assays for miR-221/222 promoter, 3'UTR reporter for TIMP3, rescue experiments Cell death & disease Medium 29789601
2022 miR-24-3p promotes skeletal muscle differentiation by directly targeting HMGA1 mRNA; HMGA1 in turn regulates ID3 expression; the miR-24-3p/HMGA1/ID3 axis controls muscle stem cell (satellite cell) differentiation and skeletal muscle regeneration in vivo. Direct 3'UTR targeting validated, miR-24-3p knockdown in neonatal mice, tibialis anterior muscle regeneration model in vivo Cellular and molecular life sciences Medium 35238991
2019 Cytoplasmic HMGA1 in glioma cells interacts with vimentin; this interaction is required for the migration and invasion-promoting effect of HMGA1 overexpression, as vimentin inhibition abolishes HMGA1-induced increased migration. Co-immunoprecipitation of cytoplasmic HMGA1 and vimentin, functional rescue with vimentin inhibition Molecular therapy. Nucleic acids Medium 33614228
2022 IGF2BP2 directly binds HMGA1 mRNA, augments its stability, and increases HMGA1 protein expression; the IGF2BP2/HMGA1 axis promotes epithelial-to-mesenchymal transition and metastasis in gastric cancer. RNA immunoprecipitation (RIP) for IGF2BP2-HMGA1 mRNA interaction, mRNA stability assay, in vitro and in vivo metastasis models Cancers Medium 36358799

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 HMGI/Y proteins: flexible regulators of transcription and chromatin structure. Biochimica et biophysica acta 312 11406267
2005 Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nature medicine 176 15924147
2019 PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways. Cancer letters 162 30776481
2012 MicroRNA-137, an HMGA1 target, suppresses colorectal cancer cell invasion and metastasis in mice by directly targeting FMNL2. Gastroenterology 117 23201162
2013 HMGA1 promotes metastatic processes in basal-like breast cancer regulating EMT and stemness. Oncotarget 114 23945276
2016 The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development. Current molecular medicine 101 26980699
2006 Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice. Cancer research 93 16510570
2019 HMGA1 in cancer: Cancer classification by location. Journal of cellular and molecular medicine 89 30614613
2002 Thyroid cell transformation requires the expression of the HMGA1 proteins. Oncogene 77 12082527
2009 HMGA1 correlates with advanced tumor grade and decreased survival in pancreatic ductal adenocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 73 19820691
2011 Functional variants of the HMGA1 gene and type 2 diabetes mellitus. JAMA 72 21364139
2010 Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion. Clinical cancer research : an official journal of the American Association for Cancer Research 72 21138859
2009 Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas. Human pathology 71 20004941
2003 HMGA1 protein over-expression is a frequent feature of epithelial ovarian carcinomas. Carcinogenesis 71 12807722
2003 Loss of Hmga1 gene function affects embryonic stem cell lympho-hematopoietic differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 69 12824305
2009 Two new miR-16 targets: caprin-1 and HMGA1, proteins implicated in cell proliferation. Biology of the cell 67 19250063
2004 HMGA1 protein overexpression in human breast carcinomas: correlation with ErbB2 expression. Clinical cancer research : an official journal of the American Association for Cancer Research 66 15569996
2019 HMGA1 promotes breast cancer angiogenesis supporting the stability, nuclear localization and transcriptional activity of FOXM1. Journal of experimental & clinical cancer research : CR 64 31311575
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