Affinage

HLA-DRA

HLA class II histocompatibility antigen, DR alpha chain · UniProt P01903

Length
254 aa
Mass
28.6 kDa
Annotated
2026-06-10
80 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HLA-DRA encodes the invariant α-chain of the HLA-DR class II MHC heterodimer, which pairs with a DRB β-chain to present peptide antigens to CD4+ T cells; recombinant DRA/DRB heterodimers reconstituted in heterologous cells bind peptide with native specificity and affinity and productively stimulate restricted T cells (PMID:9510368), and DRA-driven surface class II in thymic epithelium is sufficient to delete superantigen- and DR-peptide-reactive T cells, establishing a role in central tolerance (PMID:8100779). The peptide-presenting α-chain identity modulates, but does not dictate, superantigen engagement, which is governed primarily by the β-chain (PMID:8244778). The dominant theme of the corpus is transcriptional control of HLA-DRA through a conserved proximal module of W, X1, X2, and Y cis-elements that must remain precisely spaced and helically phased to assemble a single cooperative complex required for both constitutive and inducible expression (PMID:1560213, PMID:1331098). RF-X occupies the X1 box, correlating with class II DNase I hypersensitivity and lost in class II–deficient immunodeficiency mutants, marking it as necessary but not sufficient for expression (PMID:2467188, PMID:1903200), while additional X-box-region factors (X2BP, hXBP-1, TRAX1) and the Y-box factor NF-Y act through the same module (PMID:1956787, PMID:8349596, PMID:7799935, PMID:2278044). CIITA serves as the master coordinator, recruiting distinct histone acetyltransferase activities—directing H4 (Lys8) and H3 acetylation through separable domains—and, together with RFX, establishing reduced nucleosome density and heritable histone modification patterns across the locus (PMID:11429551, PMID:22701520). IFN-γ induces expression specifically by strengthening protein–DNA contacts at the X1/X2 boxes (PMID:1502171), with cell-type-specific and stimulus-specific factors layered on top: an astrocyte IFN-γ–induced X-element factor and TNF-α synergy complex (PMID:1588050, PMID:1454841), an Rb requirement for DRA induction with Oct-1 acting as a repressor that excludes NF-Y in Rb-defective cells (PMID:15105429, PMID:8786310), and an NF-κB requirement specific to TLR-driven (but not IFN-γ–driven) induction (PMID:16619292). Post-transcriptionally, a 3′ UTR signal mediates nuclear retention of HLA-DRA mRNA (PMID:8028004), and a splice-acceptor variant (rs8084) produces a short ER-retained isoform that lacks 25 extracellular residues and, rather than reaching the surface alone, binds the outer peptide-binding domain of canonical HLA-DR heterodimers via an exposed loop (F76) and allosterically reshapes the peptide-binding pocket (PMID:32986852, PMID:35218721). In disease and tissue contexts, HLA-DRA expression is induced by cuproptosis-driven ROS and promotes T-cell-infiltrating chemokine production that synergizes with anti-PD-1 therapy in ccRCC (PMID:38931345), and modulates JAK-STAT inflammatory signaling and radiosensitivity in irradiated epithelial cells (PMID:41956771).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1989 High

    Establishing which trans-acting factor licenses class II chromatin addressed why some cells fail to express HLA-DRA despite an intact promoter.

    Evidence DNase I hypersensitivity mapping and RF-X binding across normal B cells, class II–deficient mutants, and fibroblasts

    PMID:2467188

    Open questions at the time
    • RF-X binding necessary but not sufficient for expression
    • additional factors enabling fibroblast/IFN-γ competence not identified
  2. 1990 Medium

    Dissecting the proximal promoter elements clarified that the Y box and X-box-binding proteins exert non-redundant positive and negative control over transcription.

    Evidence Cell-free in vitro transcription with Y-box/octamer deletions; competition EMSA mapping W and V elements to X-box-binding proteins

    PMID:2120707 PMID:2278044

    Open questions at the time
    • identity of the shared X/W/V-binding proteins not resolved
    • octamer factor usage distinct from immunoglobulin promoters but mechanism unclear
  3. 1991 Medium

    Mapping the precise nucleotides and protein complexes at the X and W boxes defined the molecular grammar of factor recognition and linked binding affinity to expression level.

    Evidence Single-bp substitutions with natural and recombinant RF-X; EMSA distinguishing RFX (X1) from X2BP (X2); UV cross-linking of the X-A complex; W-element reporter/EMSA across cell types

    PMID:1903200 PMID:1904083 PMID:1956787 PMID:1991973

    Open questions at the time
    • molecular identities of X-A complex subunits (22/32/82/92 kDa) not cloned
    • basis for tissue-restricted expression beyond differential binding unexplained
  4. 1992 High

    Systematic mutagenesis and IFN-γ footprinting resolved how a single cooperative complex on geometrically constrained elements drives both constitutive and inducible expression.

    Evidence Single-bp, spacing, and helical-phasing mutants in B cells and IFN-γ-treated fibroblasts; in vivo genomic footprinting ± IFN-γ; astrocyte IFNEX and TNF-α/IFN-γ synergy (TIC-X) EMSA

    PMID:1331098 PMID:1454841 PMID:1502171 PMID:1560213 PMID:1588050

    Open questions at the time
    • IFNEX and TIC-X factors not molecularly identified
    • structural model of the X/Y stem-loop complex not determined
  5. 1993 Medium

    Functional and genetic tests established the protein product's role in antigen presentation, central tolerance, and the relative contribution of the α-chain to superantigen engagement.

    Evidence HLA-DRA transgenic mice with tissue-restricted expression; TCR Vβ repertoire and tolerance assays; hXBP-1 X2 cross-competition EMSA

    PMID:8100779 PMID:8244778 PMID:8349596

    Open questions at the time
    • mechanism of thymic-epithelial clonal deletion incompletely defined
    • extent of hXBP-1 autoregulatory contribution to DRA in vivo unquantified
  6. 1995 High

    Affinity purification of a novel X1-binding activator extended the cast of transcription factors converging on the X box.

    Evidence Affinity purification from HeLa extracts; footprinting, UV cross-linking, and in vitro transcription showing TRAX1 activation

    PMID:7799935

    Open questions at the time
    • TRAX1 gene identity and interplay with RFX/CIITA not established
    • in vivo requirement not tested
  7. 1996 Medium

    Identifying an Rb requirement and a 3′ UTR retention signal added a tumor-suppressor input and a post-transcriptional control layer to DRA regulation.

    Evidence RB reconstitution in RB-defective tumor cells with mRNA/surface readouts; 3′ UTR deletion with nuclear/cytoplasmic fractionation and RNA-protein binding

    PMID:8028004 PMID:8786310

    Open questions at the time
    • molecular step at which Rb acts on DRA induction unclear
    • identity of the 3′ UTR-binding retention proteins unknown
  8. 2004 High

    Defining Oct-1 as a repressor that excludes NF-Y explained how Rb-defective cells silence inducible HLA-DRA.

    Evidence ChIP of endogenous promoter, Oct-1 antisense knockdown, DRAN complex analysis, and TSA treatment

    PMID:15105429

    Open questions at the time
    • link between Rb status and Oct-1 recruitment not fully mechanistic
    • generality beyond Rb-defective tumor cells untested
  9. 2006 High

    Distinguishing TLR/NF-κB-dependent from IFN-γ-dependent induction showed CIITA is necessary but not sufficient for all activation routes.

    Evidence Dominant-negative CIITA, CIITA siRNA, NF-κB inhibition, ChIP, and EMSA in human B cells

    PMID:16619292

    Open questions at the time
    • how NF-κB cooperates physically with CIITA/RFX at the promoter unresolved
  10. 2012 High

    Profiling chromatin state across the locus integrated RFX/CIITA factor binding with specific histone-modifying complexes and demonstrated heritable epigenetic memory of induction.

    Evidence Dual-crosslinking ChIP of multiple histone marks, RFX/CIITA mutant B-cell lines, MLL and GCN5 complex component detection, cell-division tracking

    PMID:22701520

    Open questions at the time
    • mechanism maintaining marks through division not defined
    • CIITA-independent MLL recruitment route unclear
  11. 2020 Medium

    Characterizing a splice-acceptor variant revealed a non-canonical short isoform that piggybacks on full-length heterodimers and allosterically modulates peptide binding.

    Evidence Splice-variant identification, trafficking/fractionation assays, co-expression with canonical heterodimers, MD simulations, and F76 mutational validation

    PMID:32986852 PMID:35218721

    Open questions at the time
    • functional/immunological consequence of pocket allostery in vivo not measured
    • structural claims rest substantially on MD simulation
  12. 2024 Medium

    Linking HLA-DRA to tumor immunity and tissue remodeling positioned its expression as a functional driver of inflammatory and disease phenotypes.

    Evidence Cuproptosis/ROS induction with chemokine and T-cell-infiltration readouts and anti-PD-1 in vivo; CRISPR KO/OE radiosensitivity and JAK-STAT analysis; siRNA osteogenesis assays

    PMID:38931345 PMID:41721874 PMID:41956771

    Open questions at the time
    • whether phenotypes depend on antigen presentation versus non-canonical roles unresolved
    • osteogenesis finding is single low-confidence study without pathway placement

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identities of several X-box-region factors (X-A complex, IFNEX, TIC-X) and the structural architecture of the cooperative W/X/Y enhanceosome remain undefined.
  • no cloned identity for the UV-crosslinked X-A complex subunits
  • no high-resolution structure of the assembled promoter complex
  • in vivo contribution of TRAX1 and hXBP-1 not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 2
Partners
CIITANFYPOU2F1RB1RFXXBP1
Complex memberships
HLA-DR class II MHC heterodimer

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CIITA coordinates multiple histone acetyltransferase activities at the HLA-DRA promoter: a CIITA mutant lacking its activation domain induced H4 but not H3 acetylation, indicating distinct HAT activities are required for each modification; H4 acetylation was mapped to Lys8. Chromatin immunoprecipitation (ChIP) time-course in CIITA-expressing cells; CIITA activation-domain deletion mutant; histone acetylation mapping Nature immunology High 11429551
1991 Two distinct nuclear factors bind the HLA-DRA X box region in B cells: RFX binds the X1 box but binds poorly to DRB beta-chain promoters, while a separate factor X2BP binds the X2 box of DRA with high affinity and recognizes a different subset of class II promoters. Gel electrophoretic mobility shift assays (EMSA) with B-cell nuclear extracts and DRA promoter oligonucleotides Nucleic acids research Medium 1956787
1992 In vivo genomic footprinting of the HLA-DRA promoter demonstrated that IFN-γ induces class II expression in non-lymphoid glioblastoma cells by specifically up-regulating protein–DNA interactions at the X1 and X2 boxes, while leaving octamer, Y, and other contacts unchanged. In vivo genomic footprinting (DMS/ligation-mediated PCR) in B-cell lines, T-cell lines, and glioblastoma cells ± IFN-γ treatment Proceedings of the National Academy of Sciences of the United States of America High 1502171
1992 Single base-pair substitutions in the HLA-DRA promoter demonstrated that W, X1, X2, and Y boxes each contribute to maximal B-cell expression, while W, X1, and X2 are specifically required for IFN-γ induction in fibroblasts; some mutations differentially affected B-cell vs. fibroblast expression, indicating cell-type-specific factor usage. Site-directed mutagenesis of DRA promoter linked to reporter gene; transient transfection in B cells and IFN-γ-treated fibroblasts; EMSA to assess DNA–protein interactions Journal of immunology High 1560213
1992 Constitutive and IFN-γ-inducible transcription of HLA-DRA requires precise spacing between the S and X elements (any spacing change is not tolerated) and stereospecific helical alignment between X and Y elements; disruption of either constraint abolishes both constitutive B-cell expression and IFN-γ induction, implying a shared protein complex forms on all three elements. Spacing and helical-turn insertion/deletion mutants of DRA promoter; transient transfection reporter assays in B-cell lines and IFN-γ-treated fibroblasts The Journal of biological chemistry High 1331098
1990 X-box-binding proteins mediate both positive and negative transcriptional regulation of HLA-DRA: a positive W element (−135 to −117 bp) and a negative V element (−193 to −179 bp) upstream of the class II box both bind the same nuclear proteins that bind the X box, as shown by competition EMSA. 5′ promoter deletions, substitution mutants, nuclease S1 protection assays, gel-mobility-shift assays with Raji nuclear extracts Proceedings of the National Academy of Sciences of the United States of America Medium 2120707
1989 The trans-acting factor RF-X binds to the HLA-DRA promoter and its occupancy correlates with two prominent DNase I–hypersensitive sites in the class II promoter chromatin; these hypersensitive sites are absent in immunodeficient mutant B cells lacking RF-X binding, but are present in uninduced normal fibroblasts (which have normal RF-X binding), indicating RF-X binding is necessary but not sufficient for class II expression. DNase I hypersensitivity mapping; in vitro RF-X binding assays; comparison of normal B cells, class II–deficient mutant cells, and IFN-γ–induced fibroblasts Molecular and cellular biology High 2467188
1991 Single base-pair substitutions across the HLA-DRA X1 box revealed the specific nucleotide positions required for RF-X binding; several substitutions severely reduced RF-X binding for both natural and recombinant RF-X with the same specificity, and positions important for high-affinity RF-X binding correlate with high levels of class II expression. EMSA with natural and recombinant RF-X protein; systematic single-bp substitutions across the DRA X1 box Nucleic acids research High 1903200
1991 The W element (−143 to −123 bp) of the HLA-DRA promoter is a positive transcriptional regulator active in all DR+ cell types (not B-cell-specific), binding proteins W-B1 (ubiquitous) and W-B2 (lymphoid-specific); W/P-dependent activity parallels endogenous DRA transcription but tissue-restricted regulation is not accounted for solely by differential W-protein binding. Transient transfection reporter assays in multiple cell types; EMSA with W-element oligonucleotides; 5′ deletion and substitution analysis Journal of immunology Medium 1991973
1991 The X-A DNA–protein complex containing proteins of ~22, 32, 82, and 92 kDa (UV cross-linked) is required for HLA-DRA X-box-dependent transcription; this complex is absent in the immunodeficient B-cell mutant 6.1.6 and in some (but not all) patient-derived class II–negative immunodeficiency cells. Transient transfection of DRA promoter-reporter constructs; EMSA; UV cross-linking of proteins to BrdU-substituted probe; comparison of normal and mutant cell extracts Journal of immunology Medium 1904083
1992 In primary astrocytes, IFN-γ regulation of HLA-DRA requires the S, X (specifically X1), and Y elements; IFN-γ induces a novel X-element–binding nuclear factor (IFNEX) in astrocytes that is distinct from previously described factors, suggesting IFNEX mediates IFN-γ–driven class II expression in this primary cell type. Site-specific mutagenesis of DRA promoter; transient transfection reporter assay in primary astrocytes; EMSA with nuclear extracts from IFN-γ–treated astrocytes Journal of immunology Medium 1588050
1992 TNF-α alone does not activate the HLA-DRA promoter in astrocytes but synergizes with IFN-γ via formation of a novel, slower-migrating DNA–protein complex (TIC-X) at the X element; W, X, and Y elements are all required for this TNF-α enhancement of IFN-γ–induced promoter activity. Transient transfection of DRA-CAT reporter in primary astrocytes ± IFN-γ and/or TNF-α; EMSA with nuclear extracts Proceedings of the National Academy of Sciences of the United States of America Medium 1454841
1992 T-cell activation induces strong HLA-DRA promoter activity from a proximal 43-bp TATTA-containing region in primary (non-transformed) T lymphocytes; mutation of the TATTA motif greatly reduces expression; addition of X and Y elements augments early activation response but paradoxically suppresses promoter function in already-activated DR+ T cells, revealing a cell-state-dependent switch. Transient transfection of DRA-CAT reporter constructs in primary human T lymphocytes stimulated by mitogens or antigens; TATTA mutagenesis Molecular and cellular biology Medium 1448091
1993 hXBP-1, a b-ZIP transcription factor, regulates HLA-DRA through the X2 box; the hXBP-1 promoter itself contains an hX2 element identical to the X2 site in the DRA promoter, and two of four protein complexes binding the hXBP-1 hX2 site cross-compete with DRA X2-binding complexes, indicating an autoregulatory loop. EMSA cross-competition experiments; mutagenesis of hX2 site; DRA promoter mapping; hybrid cell mapping of hXBP-1 loci The Journal of biological chemistry Medium 8349596
1995 TRAX1, affinity-purified from HeLa nuclear extracts, is a novel X1-box-binding transcriptional activator of HLA-DRA (~40 kDa by UV cross-linking); it contacts the 5′ end of the X1 sequence (positions −109/−108) with hypersensitive sites at −114/−113/−97, a distinct footprint from RFX1, RFX, NF-Xc, and NF-X; it activates the HLA-DRA promoter in an in vitro transcription assay. Affinity purification from HeLa nuclear extracts; EMSA; UV cross-linking; methylation interference footprinting; in vitro transcription assay Molecular and cellular biology High 7799935
1990 In vitro transcription from the HLA-DRA promoter is completely dependent on the Y box; deletion of the Y box reduces transcription by 95%; the DRA octamer element does not utilize OTF-2 in a manner analogous to immunoglobulin promoters despite OTF-2 being present in B-cell extracts. Cell-free in vitro transcription assay using B-cell and HeLa nuclear extracts; 5′ deletion and internal deletion of Y box and octamer Tissue antigens Medium 2278044
1994 A 3′ untranslated region signal in HLA-DRA mRNA mediates nuclear retention; deletion of this region abrogates binding of compartmentalized nuclear/cytoplasmic proteins and releases HLA-DRA mRNA into the cytoplasm; the pattern of these mRNA-binding proteins differs between cell types (Raji vs. Ntera-2) and is modulated by retinoic acid. Transient transfection of DRA constructs with 3′ UTR deletions; nuclear/cytoplasmic RNA fractionation; RNA–protein binding assays with compartmentalized extracts Journal of molecular biology Medium 8028004
2004 Oct-1 represses IFN-γ inducibility of the endogenous HLA-DRA gene in Rb-defective tumor cells by occupying the HLA-DRA promoter and forming a repressive complex (DRAN) that blocks NF-Y access to the promoter; trichostatin A (HDAC inhibitor) converts the promoter to a transcriptionally competent state and displaces Oct-1. Oct-1 antisense transformants; chromatin immunoprecipitation (ChIP) of endogenous HLA-DRA promoter; in vitro DNA–protein binding (DRAN complex analysis); TSA treatment The Journal of biological chemistry High 15105429
2006 TLR-triggered (CpG-DNA and LPS) HLA-DRA expression in human B cells requires NF-κB activation at the DRA promoter in addition to CIITA; dominant-negative CIITA and CIITA siRNA show CIITA alone is insufficient for maximal TLR-induced expression, whereas NF-κB is dispensable for IFN-γ–induced class II expression. Dominant-negative CIITA expression; CIITA siRNA knockdown; NF-κB pathway inhibition; EMSA; chromatin immunoprecipitation (ChIP); promoter-reporter mutant analysis European journal of immunology High 16619292
2012 Active transcription of HLA-DRA is accompanied by reduced nucleosome density at the proximal regulatory region and distinct distributions of histone acetylation and methylation marks throughout the gene; most modifications depend on RFX or CIITA binding to the proximal regulatory region; once established after IFN-γ induction, modifications persist through multiple cell divisions (epigenetic memory). Components of MLL methyltransferase (MLL1, ASH2L, RbBP5—some CIITA-independent) and GCN5-containing acetyltransferase complexes (ATAC and STAGA) are recruited across the gene. Dual crosslinking ChIP; ChIP-seq-like profiling of multiple histone marks; RFX and CIITA mutant B-cell lines; cell division tracking after stimulus removal; identification of complex components by ChIP PloS one High 22701520
1998 Recombinant HLA-DRA1*0101/DRB1*0401 heterodimers expressed in Drosophila S2 cells are functional: they present peptides to DRB1*0401-restricted T cells, bind peptide with similar specificity and affinity to human B-cell-derived molecules, and can be stabilized by high-affinity peptide; they show decreased N-linked glycosylation compared to human-derived molecules but retain antigen-presentation capacity. Drosophila S2 cell expression; flow cytometry; T-cell stimulation assay; SDS-PAGE stability assay ± peptide; peptide-binding assay Tissue antigens High 9510368
1993 Expression of HLA-DRA in thymic epithelial cells (without bone-marrow-derived APC expression) is sufficient to drive clonal deletion of superantigen-reactive T cells bearing TCRβ-V5 and -V11, and to induce tolerance to DR-alpha-derived processed peptide/I-Ab complexes, likely via clonal deletion. Transgenic mouse lines with cell-type-restricted HLA-DRA expression (thymic epithelium only vs. all APC); TCR Vβ repertoire analysis; T-cell tolerance assays European journal of immunology High 8100779
1993 Transgenic DR-alpha/E-beta mixed isotype molecules efficiently interact with Mtv-7 superantigen to delete V-beta-6+ and V-beta-7+ T cells; deletion of V-beta-11+ T cells with Mtv-8/9 was less efficient than with H-2Ea transgenes, demonstrating that the alpha-chain identity influences superantigen interaction but the beta-chain identity is the critical determinant. HLA-DRA transgenic mice on various mouse Mtv-bearing backgrounds; TCR Vβ repertoire analysis by flow cytometry and Southern blot Human immunology Medium 8244778
1996 The retinoblastoma protein (Rb) is required for IFN-γ induction of HLA-DRA (and other class II) mRNA in non-small-cell lung carcinoma cells; RB reconstitution rescues DRB inducibility but not DRA inducibility in H2009 subclones, explaining the lack of surface HLA-DR expression, and this Rb requirement operates independently of Rb's role in inhibiting apoptosis. RB reconstitution in RB-defective H2009 tumor cell subclones; Northern blot analysis of class II mRNAs; surface HLA-DR flow cytometry; CIITA mRNA analysis Journal of immunology Medium 8786310
2020 A splice-acceptor variant (rs8084) in HLA-DRA mediates transcription of a short HLA-DRA isoform (sHLA-DRA) lacking 25 amino acids in the extracellular domain; molecular dynamics simulations predict structural refolding affecting stability and trafficking; experimentally, sHLA-DRA cannot reach the cell surface independently but is retained in the ER for degradation, yet can be transported to the membrane via binding to the peptide-binding site of canonical full-length HLA heterodimers. Splice-variant identification; molecular dynamics simulations; cellular fractionation/trafficking assays; co-expression with canonical HLA-DR heterodimers; flow cytometry Immunology Medium 32986852
2022 The short HLA-DRA isoform (sHLA-DRA) binds to the outer domain of the HLA-DR2 peptide-binding site via a loop region (residues R69–G83) exposed only in the short isoform; the critical residue F76 mediates this interaction (experimentally validated); sHLA-DRA allosterically modifies the peptide-binding pocket conformation of canonical HLA-DR2 heterodimers. Atomistic molecular dynamics simulations; mutational validation of F76 residue; functional binding assays Archives of biochemistry and biophysics Medium 35218721
2024 Cuproptosis upregulates HLA-DRA expression at the transcriptional level in a dose-dependent manner in ccRCC cells by inducing reactive oxygen species (ROS) production; high HLA-DRA expression promotes chemokine (CCL5, CXCL9, CXCL10) expression in the tumor microenvironment, enhances CD4+ and CD8+ T-cell infiltration, and synergizes with anti-PD-1 immunotherapy to suppress tumor growth in vivo. In vitro cuproptosis induction in ccRCC cells; dose-response RT-PCR/Western blot for HLA-DRA; siRNA knockdown; chemokine ELISA; in vivo mouse tumor model with anti-PD-1 treatment; flow cytometry for T-cell infiltration Pharmaceuticals (Basel, Switzerland) Medium 38931345
2026 siRNA knockdown of HLA-DRA in human valvular interstitial cells (VICs) under osteogenic stimulation reduces mineral deposition, alkaline phosphatase (ALP) activity, and VIC proliferation, indicating HLA-DRA functionally drives osteogenic remodeling in vitro. siRNA knockdown of HLA-DRA in human VICs; osteogenic stimulation; Alizarin Red S staining; ALP activity assay; CCK-8 proliferation assay; RT-qPCR; Western blot Journal of computer-aided molecular design Low 41721874
2026 HLA-DRA overexpression in nasal mucosal epithelial cells increases radiosensitivity (reduced clonogenic survival, enhanced apoptosis, suppressed proliferation after irradiation) and elevates IFN-γ and IL-6 production, which activates JAK-STAT signaling; HLA-DRA knockout has the opposite effects, implicating HLA-DRA in regulating the JAK-STAT inflammatory pathway in irradiated epithelial cells. CRISPR/Cas9 HLA-DRA knockout and overexpression in nasal mucosal epithelial cells; X-ray irradiation; colony formation assay; CCK-8; flow cytometry (apoptosis); RT-qPCR; ELISA; Western blot for STAT phosphorylation Zhonghua er bi yan hou tou jing wai ke za zhi Medium 41956771
1999 Nuclear factor NF-Y binds to Y-box sequences in both the proximal promoter and the far-upstream region of HLA-DRA (Y′ box), as demonstrated by antibody supershift in gel-retardation assays; similar proteins bind to Y and Y′ boxes and to X and X′ boxes, supporting a model in which protein dimerization across these elements induces a DNA stem-loop bringing the far-upstream and proximal-promoter regions into proximity. DNase I footprinting; gel retardation (EMSA); antibody supershift for NF-Y identification Biochimie Low 10385003

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 CIITA coordinates multiple histone acetylation modifications at the HLA-DRA promoter. Nature immunology 152 11429551
1991 Two B cell factors bind the HLA-DRA X box region and recognize different subsets of HLA class II promoters. Nucleic acids research 73 1956787
1992 In vivo footprint analysis of the HLA-DRA gene promoter: cell-specific interaction at the octamer site and up-regulation of X box binding by interferon gamma. Proceedings of the National Academy of Sciences of the United States of America 68 1502171
2014 HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping. The Journal of allergy and clinical immunology 65 25224099
1992 Single base pair substitutions within the HLA-DRA gene promoter separate the functions of the X1 and X2 boxes. Journal of immunology (Baltimore, Md. : 1950) 64 1560213
2010 Greater expression of TLR2, TLR4, and IL6 due to negative energy balance is associated with lower expression of HLA-DRA and HLA-A in bovine blood neutrophils after intramammary mastitis challenge with Streptococcus uberis. Functional & integrative genomics 59 20072847
1992 Structural constraints within a trimeric transcriptional regulatory region. Constitutive and interferon-gamma-inducible expression of the HLA-DRA gene. The Journal of biological chemistry 50 1331098
2013 Preliminary results in quantitation of HLA-DRA by real-time PCR: a promising approach to identify immunosuppression in sepsis. Critical care (London, England) 48 24093602
1990 X-box-binding proteins positively and negatively regulate transcription of the HLA-DRA gene through interaction with discrete upstream W and V elements. Proceedings of the National Academy of Sciences of the United States of America 46 2120707
1992 Usage of primary cells to delineate IFN-gamma-responsive DNA elements in the HLA-DRA promoter and to identify a novel IFN-gamma-enhanced nuclear factor. Journal of immunology (Baltimore, Md. : 1950) 39 1588050
1991 Transcriptional regulation of the HLA-DRA gene. Critical reviews in immunology 39 1930684
1989 Inherited immunodeficiency with a defect in a major histocompatibility complex class II promoter-binding protein differs in the chromatin structure of the HLA-DRA gene. Molecular and cellular biology 39 2467188
1996 Apoptosis-independent retinoblastoma protein rescue of HLA class II messenger RNA IFN-gamma inducibility in non-small cell lung carcinoma cells. Lack of surface class II expression associated with a specific defect in HLA-DRA induction. Journal of immunology (Baltimore, Md. : 1950) 38 8786310
1992 Localization of IFN-gamma receptor in first trimester placenta to trophoblasts but lack of stimulation of HLA-DRA, -DRB, or invariant chain mRNA expression by IFN-gamma. Journal of immunology (Baltimore, Md. : 1950) 38 1401907
1991 Defective HLA DRA X box binding in the class II transactive transcription factor mutant 6.1.6 and in cell lines from class II immunodeficient patients. Journal of immunology (Baltimore, Md. : 1950) 36 1904083
1991 The W element is a positive regulator of HLA-DRA transcription in various DR+ cell types. Journal of immunology (Baltimore, Md. : 1950) 36 1991973
2006 Direct role of NF-kappaB activation in Toll-like receptor-triggered HLA-DRA expression. European journal of immunology 35 16619292
1992 Tumor necrosis factor alpha response elements in the HLA-DRA promoter: identification of a tumor necrosis factor alpha-induced DNA-protein complex in astrocytes. Proceedings of the National Academy of Sciences of the United States of America 32 1454841
1991 Regulatory factor-X binding to mutant HLA-DRA promoter sequences. Nucleic acids research 31 1903200
2022 HLA class II molecule HLA-DRA identifies immuno-hot tumors and predicts the therapeutic response to anti-PD-1 immunotherapy in NSCLC. BMC cancer 29 35794593
2019 Insights into the polymorphism in HLA-DRA and its evolutionary relationship with HLA haplotypes. HLA 28 31617688
1995 A novel Creb family gene telomeric of HLA-DRA in the HLA complex. Genomics 25 8586413
2010 Multiple sclerosis risk markers in HLA-DRA, HLA-C, and IFNG genes are associated with sex-specific childhood leukemia risk. Autoimmunity 23 21067287
2003 Relative quantification of HLA-DRA1 and -DQA1 expression by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 23 12648283
2004 Oct-1 maintains an intermediate, stable state of HLA-DRA promoter repression in Rb-defective cells: an Oct-1-containing repressosome that prevents NF-Y binding to the HLA-DRA promoter. The Journal of biological chemistry 22 15105429
2022 Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer. Cellular oncology (Dordrecht, Netherlands) 21 35543859
1992 Activation of the HLA-DRA gene in primary human T lymphocytes: novel usage of TATA and the X and Y promoter elements. Molecular and cellular biology 20 1448091
2014 HLA-DRA is associated with Parkinson's disease in Iranian population. International journal of immunogenetics 19 25319953
2022 CD74 and HLA-DRA in Cervical Carcinogenesis: Potential Targets for Antitumour Therapy. Medicina (Kaunas, Lithuania) 18 35208514
2019 Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes. Diabetes 18 30962219
1991 Description of a polymorphism in the regulatory region of the HLA-DRA gene. Human immunology 18 1685491
1990 Functional analysis of cis-linked regulatory sequences in the HLA DRA promoter by transcription in vitro. Tissue antigens 17 2278044
2017 New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population-The genome-wide association study. European journal of obstetrics, gynecology, and reproductive biology 16 28881265
2012 Multiple histone methyl and acetyltransferase complex components bind the HLA-DRA gene. PloS one 16 22701520
1998 Functional characterization of HLA-DRA1*0101/DRB1*0401 molecules expressed in Drosophila melanogaster cells. Tissue antigens 16 9510368
1993 The regulatory gene, hXBP-1, and its target, HLA-DRA, utilize both common and distinct regulatory elements and protein complexes. The Journal of biological chemistry 16 8349596
2013 Reaffirmation of GAK, but not HLA-DRA, as a Parkinson's disease susceptibility gene in a Taiwanese population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 15 24039160
2012 HLA-DRA polymorphisms associated with risk of nasal polyposis in asthmatic patients. American journal of rhinology & allergy 15 22391069
1999 HLA-DMB gene and HLA-DRA promoter region polymorphisms in Australian multiple sclerosis patients. Human immunology 15 10527398
2016 HLA-DRA/HLA-DRB5 polymorphism affects risk of sporadic ALS and survival in a southwest Chinese cohort. Journal of the neurological sciences 13 28131168
1993 T-cell repertoire in a strain of transgenic C57BL/6 mice with the HLA-DRA gene on the X-chromosome. Immunogenetics 13 8420827
1993 Mouse mammary tumor virus-mediated T-cell receptor negative selection in HLA-DRA transgenic mice. Human immunology 12 8244778
1994 Control of nucleo-cytoplasmic HLA-DRA mRNA partitioning by interaction of a retention signal with compartmentalized proteins. Journal of molecular biology 11 8028004
1993 Restricted expression of transgenic HLA-DRA gene in thymic epithelial cells and its role in acquisition of T cell tolerance to self-superantigens and processed DR alpha-derived peptide. European journal of immunology 11 8100779
1991 Tissue-specific expression of the HLA-DRA gene in transgenic mice. Immunogenetics 11 1721044
1995 Affinity enrichment and functional characterization of TRAX1, a novel transcription activator and X1-sequence-binding protein of HLA-DRA. Molecular and cellular biology 10 7799935
2024 Improved Immunotherapy Outcomes via Cuproptosis Upregulation of HLA-DRA Expression: Promoting the Aggregation of CD4+ and CD8+T Lymphocytes in Clear Cell Renal Cell Carcinoma. Pharmaceuticals (Basel, Switzerland) 9 38931345
1995 Sequencing of an upstream region of the human HLA-DRA gene containing X' and Y' boxes. Nucleic acids research 9 7784170
2022 HLA-DRA Gene Polymorphisms Are Associated with Graves' Disease as an Autoimmune Thyroid Disease. BioMed research international 8 36132072
2021 Tri-SNP polymorphism in the intron of HLA-DRA1 affects type 1 diabetes susceptibility in the Finnish population. Human immunology 8 34311991
1991 Transcriptional regulation of HLA-DRA gene. Research in immunology 8 1754710
1997 HLA-DRA promoter polymorphism and diversity generation within the immune system. Human genetics 7 9187677
2020 Analysis of Single Nucleotide Polymorphisms in HLA-DRA, IL2RA , and HMGB1 Genes in Multiple Sclerosis. Reports of biochemistry & molecular biology 6 33178870
2017 Expression of HLA-DRA and CD74 mRNA in whole blood during the course of complicated and uncomplicated Staphylococcus aureus bacteremia. Microbiology and immunology 6 28862321
2022 Genetic polymorphism of HLA-DRA and alcohol consumption affect hepatitis development in the Korean population. Genes & genomics 4 35895219
2020 A splice acceptor variant in HLA-DRA affects the conformation and cellular localization of the class II DR alpha-chain. Immunology 4 32986852
2015 Association analysis of HLA-DRA in Chinese patients with sporadic Parkinson's disease. International journal of physiology, pathophysiology and pharmacology 4 27073595
2002 The HLA-DRA*0102 allele: correct nucleotide sequence and associated HLA haplotypes. Tissue antigens 4 12445311
1999 Analysis of the human HLA-DRA gene upstream region: evidence for a stem-loop array directed by nuclear factors. Biochimie 4 10385003
1997 In vitro and in vivo evidence for high frequency of I-Ab-reactive CD4+ T cells in HLA-DQ or HLA-DRA transgenic mice lacking endogenous MHC class I and/or class II expression. Journal of immunology (Baltimore, Md. : 1950) 4 9378957
2024 Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease. Scientific reports 3 38942763
2022 Possible Relationship between the HLA-DRA1 Intron Haplotype of Three Single-Nucleotide Polymorphisms in Intron 1 of the HLA-DRA1 Gene and Autoantibodies in Children at Increased Genetic Risk for Autoimmune Type 1 Diabetes. ImmunoHorizons 3 35981747
2012 Common variants in HLA-DRA gene are associated with alcohol dependence in two Caucasian samples. Journal of molecular neuroscience : MN 3 22890421
2006 Korean BAC library construction and characterization of HLA-DRA, HLA-DRB3. Journal of biochemistry and molecular biology 3 16889686
2026 Single-nucleus and machine-learning integration identifies HLA-DRA and FTL as immune-metabolic axes and traditional Chinese medicine-targetable hubs in calcific aortic valve disease. Journal of computer-aided molecular design 2 41721874
2025 Effects of HLA-DRA, HLA-DQA1 and IL-6 Gene Variations to Glatiramer Acetate Resistance in Multiple Sclerosis Patients. Biochemical genetics 2 40072812
2021 Identification of three novel HLA-DRA alleles by next-generation sequencing. HLA 2 34402606
2009 Technological advances in the study of HLA-DRA promoter regulation: extending the functions of CIITA, Oct-1, Rb, and RFX. Acta biochimica et biophysica Sinica 2 19280058
2005 Modular usage of the HLA-DRA promoter in extra-hematopoietic and hematopoietic cell types of transgenic mice. The FEBS journal 2 15955077
2022 A short HLA-DRA isoform binds the HLA-DR2 heterodimer on the outer domain of the peptide-binding site. Archives of biochemistry and biophysics 1 35218721
2020 The rs3129882/rs4248166 in HLA-DRA and rs34372695 in SYT11 are not associated with sporadic Parkinson's disease in Central Chinese population. The International journal of neuroscience 1 32253955
2026 Polymorphisms in intron 1 of HLA-DRA differentially associate with type 1 diabetes and celiac disease and implicate involvement of complement system genes C4A and C4B. eLife 0 41627183
2026 [Study on mechanism underlying the role of HLA-DRA in promoting radiation-induced sinusitis]. Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery 0 41956771
2026 Identification of the Novel HLA-DRA*01:20 Allele by Single Molecule, Real-Time DNA Sequencing. HLA 0 41989255
2025 Association of HLA-DRA, HLA-DQA1, and IL-6 gene variations with susceptibility to multiple sclerosis. Molecular biology reports 0 40643781
2025 Role of HLA-DRA-CREB3L4 regulatory axis in the pathogenesis of ovarian endometriosis: Inhibition of CREB3L4 expression by HLA-DRA increases the risk of disease. Journal of reproductive immunology 0 41232153
2023 The Human Brainome: changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease. Research square 0 38168398
2003 Identification of a novel DNase I hypersensitive site within the far upstream region of the human HLA-DRA gene. International journal of molecular medicine 0 14612968
1992 [Functional expression of xenogenic mixed isotype molecule, DR alpha E beta, in transgenic mice with HLA-DRA gene on X chromosome]. Fukuoka igaku zasshi = Hukuoka acta medica 0 1534306
1991 Methylation state of the human HLA-DRa gene in transgenic mice. Cytotechnology 0 22358954

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