HMGB2

Summary

HMGB2 (high mobility group box 2, HGNC:5000) is a protein-coding gene on chromosome 4q34.1, encoding High mobility group protein B2 (P26583). Multifunctional protein with various roles in different cellular compartments.

This gene encodes a member of the non-histone chromosomal high mobility group protein family. The proteins of this family are chromatin-associated and ubiquitously distributed in the nucleus of higher eukaryotic cells. In vitro studies have demonstrated that this protein is able to efficiently bend DNA and form DNA circles. These studies suggest a role in facilitating cooperative interactions between cis-acting proteins by promoting DNA flexibility. This protein was also reported to be involved in the final ligation step in DNA end-joining processes of DNA double-strand breaks repair and V(D)J recombination.

Source: NCBI Gene 3148 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 17 total
• Druggable target: yes
• Transcription factor: yes — 11 downstream targets (CollecTRI)
• MANE Select transcript: NM_002129

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5000
Approved symbol	HMGB2
Name	high mobility group box 2
Location	4q34.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164104
Ensembl biotype	protein_coding
OMIM	163906
Entrez	3148

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 17 protein_coding, 1 retained_intron

ENST00000296503, ENST00000438704, ENST00000446922, ENST00000506267, ENST00000511316, ENST00000907095, ENST00000907096, ENST00000920462, ENST00000920463, ENST00000920464, ENST00000920465, ENST00000920466, ENST00000920467, ENST00000920468, ENST00000920469, ENST00000920470, ENST00000920471, ENST00000920472

RefSeq mRNA: 3 — MANE Select: NM_002129 NM_001130688, NM_001130689, NM_002129

CCDS: CCDS3816

Canonical transcript exons

ENST00000296503 — 5 exons

Exon	Start	End
ENSE00001081467	173333069	173333214
ENSE00001081469	173332821	173332995
ENSE00002070995	173334272	173334358
ENSE00002081308	173331376	173332238
ENSE00003657226	173333500	173333669

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 185.7169 / max 7145.7514, expressed in 1821 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54856	164.8015	1817
54857	9.7455	1465
54858	7.1402	1477
54853	1.9008	726
54855	1.6075	626
54854	0.5214	214

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.83	gold quality
secondary oocyte	CL:0000655	99.69	gold quality
amniotic fluid	UBERON:0000173	99.68	gold quality
embryo	UBERON:0000922	99.64	gold quality
trabecular bone tissue	UBERON:0002483	99.63	gold quality
ganglionic eminence	UBERON:0004023	99.63	gold quality
bone marrow	UBERON:0002371	99.54	gold quality
endometrium epithelium	UBERON:0004811	99.53	gold quality
esophagus squamous epithelium	UBERON:0006920	99.48	gold quality
tibia	UBERON:0000979	99.45	gold quality
oocyte	CL:0000023	99.43	gold quality
thymus	UBERON:0002370	99.33	gold quality
germinal epithelium of ovary	UBERON:0001304	99.17	gold quality
bone marrow cell	CL:0002092	99.10	gold quality
epithelium of nasopharynx	UBERON:0001951	98.98	gold quality
monocyte	CL:0000576	98.80	gold quality
mononuclear cell	CL:0000842	98.78	gold quality
vermiform appendix	UBERON:0001154	98.77	gold quality
leukocyte	CL:0000738	98.74	gold quality
caecum	UBERON:0001153	98.74	gold quality
right testis	UBERON:0004534	98.66	gold quality
squamous epithelium	UBERON:0006914	98.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.61	gold quality
left testis	UBERON:0004533	98.54	gold quality
lymph node	UBERON:0000029	98.50	gold quality
calcaneal tendon	UBERON:0003701	98.50	gold quality
cartilage tissue	UBERON:0002418	98.49	gold quality
pigmented layer of retina	UBERON:0001782	98.36	gold quality
gingival epithelium	UBERON:0001949	98.36	gold quality
parietal pleura	UBERON:0002400	98.33	gold quality

Single-cell (SCXA)

Detected in 78 experiment(s), a significant marker in 69.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	8380.00
E-MTAB-8894	yes	7338.35
E-HCAD-6	yes	6075.92
E-MTAB-10485	yes	5950.33
E-CURD-79	yes	5907.90
E-HCAD-5	yes	3913.27
E-GEOD-124472	yes	3796.39
E-MTAB-9906	yes	3792.63
E-MTAB-11121	yes	3785.45
E-MTAB-9435	yes	3696.57
E-MTAB-6505	yes	3529.78
E-GEOD-114530	yes	3410.62
E-HCAD-56	yes	3298.81
E-HCAD-10	yes	3108.98
E-MTAB-8410	yes	2995.76

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

11 targets.

Target	Regulation
BAX
CDKN1A
ERCC3
GFI1B	Activation
HFM1
HMGB2
MDM2
TBXT
TNF	Activation
TNNC1
TP73

Upstream regulators (CollecTRI, top): HMGB2

miRNA regulators (miRDB)

100 targeting HMGB2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192

Literature-anchored findings (GeneRIF, showing 40)

• ubiquitously expressed HMGB1 and HMGB2 have potential to cell- and promoter-specifically down- or up-regulate in vivo transcriptional activity of different members of the p53 family (PMID:11748232)
• HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. (PMID:11909973)
• binds specifically to the first AT-rich region flanking the hypersensitive site 2 core sequence of the human beta-globin gene locus control region (PMID:12555809)
• interaction of estrogen receptor alpha and beta with HMGB requires the C-terminal extension (CTE) of the estrogen receptor alpha and beta DNA binding domain (PMID:14739282)
• biophysical analysis of HMG domain from human HMGB2 binding to DNA (PMID:15833996)
• HMG2 was determined in humans. (PMID:17406091)
• single and double box proteins increase DNA flexibility and stability, albeit both effects are achieved at much lower protein concentrations for the double box. (PMID:17964600)
• In human and murine cartilage, there is an aging-related loss of HMGB2 expression, ultimately leading to its complete absence. (PMID:19139395)
• Results suggest a mechanism of up-regulation of cellular expression of topo IIalpha by HMGB1/2 in pRb-negative cells by modulation of binding of transcription factor NF-Y to the topo IIalpha promoter. (PMID:19223331)
• An isolated HMG box A domain from human HMGB2 does not enhance DNA flexibility. Substitution of a small number of cationic residues from the N-terminal leader of a functional yeast box B protein, Nhp6Ap, confers the ability to enhance DNA flexibility. (PMID:19236006)
• HMGB2 potentiates GATA-1-dependent transcription of GFI1B by Oct-1 and thereby controls erythroid differentiation. (PMID:19965638)
• Our findings collectively suggest that HMGB2 could stabilize p53 by interfering with E6/E6AP-mediated p53 degradation in HPV-positive HeLa cells. (PMID:20036050)
• The results can partly be explained by altered cell proliferations by HMGB2 associated with the antiapoptotic pathway. (PMID:20851854)
• The age-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations. (PMID:21890638)
• Crohn’s disease in the colon and ulcerative colitis can be differentially diagnosed using anti-HMGB/HMGB2 antibodies combined with anti-Saccharomyces cerevisiae antibodies. (PMID:22644337)
• Transient local HMGB2-DNA contacts dominate the DNA-bending mechanism used by HMGB proteins to increase DNA flexibility. (PMID:23143110)
• HMGB2 is necessary to protect colorectal cancer cells from DNA damage and efficient DNA repair and p53-mediated downregulation is a critical mechanism of modulating HMGB2 expression. (PMID:23255232)
• The present data suggest that HMGB2 expression is a significant prognostic factor for glioblastoma and might play an important role in cell invasion. (PMID:23828241)
• This study found that single nucleotide polymorphisms of HMGB1 may serve as potential biomarkers for predicting the efficacy of platinum-based chemotherapy. (PMID:24684392)
• the combination of a HMGB1+ and HMGB2- expression potentially predicts a poor prognosis in patients with pancreatic ductal adenocarcinoma (PMID:25060178)
• Data show that odulation of RNA helicase DDX18 directly affects growth of tamoxifen-resistant cells, suggesting that it may be a critical downstream effector of the estrogen receptors (ERs) and high mobility group box 2 (HMGB2) complex. (PMID:25284587)
• siRNA-mediated silencing of HMGB2 increased the sensitivity of the head and neck squamous cell carcinoma cell lines to cisplatin and 5-fluorouracil. (PMID:25327479)
• Lrp1-antisense directly binds to high-mobility group box 2 (Hmgb2) and inhibits the activity of Hmgb2 to enhance Srebp1a-dependent transcription of Lrp1. (PMID:25937287)
• data demonstrate a reciprocal relationship between Hmgb2 and Ctcf in controlling aspects of chromatin structure and gene expression. (PMID:27226577)
• results establish HMGB2 as a novel master regulator that orchestrates senescence-associated secretory phenotype. (PMID:27799366)
• downregulation of HMGB1 and/or HMGB2 in undifferentiated human embryonic stem cells does not affect the stemness of cells. (PMID:27863459)
• Data indicate the function of high mobility group box 2 (HMGB2) in glycolytic control in pancreatic cancer. (PMID:28069585)
• Serum HMGB2 levels were associated with in-stent restenosis in patients. (PMID:28183701)
• identified the oncogene HMGB2 as a downstream target of miR-130a by using luciferase and western blot assays. Knockdown of HMGB2 mimicked the effect of miR-130a in glioma cells. (PMID:28851665)
• Multiple functions of HMGB proteins reveal the complex roles of these proteins as innate and endogenous regulators of inflammation in joints and their cooperative roles in cartilage hypertrophy as well as in the maintenance of joint tissue homeostasis. (PMID:28916968)
• Knockdown of HMGB2 expression by stable transfected shRNA significantly decreased the growth and glycolysis of breast cancer cells both in vitro and in mouse models. (PMID:29463261)
• Authors demonstrate that HMGB2 transcription is repressed by p21 during radiation-induced senescence through the ATM-p53-p21 DNA damage signaling cascade. The loss of p21 abolished the downregulation of HMGB2 caused by ionizing radiation, and the conditional induction of p21 was sufficient to repress the transcription of HMGB2. (PMID:29487276)
• HMBG2 overexpression promotes ischemia/reperfusion-induced cell apoptosis through activating the JNK1/2-NF-kappaBp65 signaling in AC16 cardiomyocytes. (PMID:30119172)
• HMGB2 is a novel prognostic biomarker for survival in gastric cancer (PMID:30296520)
• lncRNA HOXA11-AS was overexpressed in glioma and overexpression was correlated with advanced stages of glioma and poor prognosis. Downregulating HOXA11-AS expression significantly suppressed proliferation, migration and invasion of glioma cells and increased their apoptosis. HOXA11-AS exerted its oncogenic effects by binding to miR-130a-5p, thereby neutralizing the suppressive effect of miR-130a-5p on HMGB2. (PMID:30657566)
• High-mobility group box 2 promoted proliferation of cervical cancer cells by activating AKT signaling pathway. (PMID:31209930)
• Elevated hsa-miR-590-3p expression down-regulates HMGB2 expression and contributes to the severity of IgA nephropathy. (PMID:31557418)
• Bioinformatics analysis of the prognosis and biological significance of HMGB1, HMGB2, and HMGB3 in gastric cancer. (PMID:31621076)
• impact of HMGB1/2 KD on telomerase transcriptional regulation observed in neuroectodermal cells is partially masked in hESCs by their pluripotent state. Our findings on differential roles of HMGB1 and HMGB2 proteins in regulation of telomerase activity may suggest another possible outcome of HMGB1 targeting in cells, which is currently a promising approach aiming at increasing the anticancer activity of cytotoxic agents (PMID:31661640)
• Retention of DNA topoisomerase I (TOP1) to cytoplasmic chromatin depends on its stabilization by the chromatin architecture protein HMGB2. Functionally, the HMGB2-TOP1cc-cGAS axis determines the response of orthotopically transplanted ex vivo therapy-induced senescent cells to immune checkpoint blockade in vivo. HMGB2-TOP1cc-cGAS axis enables cytoplasmic chromatin recognition and response to immune checkpoint blockade. (PMID:32075966)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmgb2a	ENSDARG00000029722
mus_musculus	Hmgb2	ENSMUSG00000054717
rattus_norvegicus	Hmgb2	ENSRNOG00000013167
rattus_norvegicus	Hmgb2l2	ENSRNOG00000029107
rattus_norvegicus	Hmgb2l1	ENSRNOG00000033321
rattus_norvegicus		ENSRNOG00000084570
caenorhabditis_elegans	hmg-3	WBGENE00001973
caenorhabditis_elegans		WBGENE00001974

Paralogs (20): HMGB3 (ENSG00000029993), HMG20B (ENSG00000064961), SP100 (ENSG00000067066), SMARCE1 (ENSG00000073584), SP140 (ENSG00000079263), TOX4 (ENSG00000092203), HMGXB4 (ENSG00000100281), TOX3 (ENSG00000103460), TFAM (ENSG00000108064), UBTF (ENSG00000108312), HMGB1P1 (ENSG00000124097), TOX2 (ENSG00000124191), SP110 (ENSG00000135899), HMG20A (ENSG00000140382), SSRP1 (ENSG00000149136), HMGB4 (ENSG00000176256), SP140L (ENSG00000185404), HMGB1 (ENSG00000189403), TOX (ENSG00000198846), UBTFL1 (ENSG00000255009)

Protein

Protein identifiers

High mobility group protein B2 — P26583 (reviewed: P26583)

Alternative names: High mobility group protein 2

All UniProt accessions (2): D6R9A6, P26583

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional protein with various roles in different cellular compartments. May act in a redox sensitive manner. In the nucleus is an abundant chromatin-associated non-histone protein involved in transcription, chromatin remodeling and V(D)J recombination and probably other processes. Binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters by enhancing transcription factor binding and/or bringing distant regulatory sequences into close proximity. Involved in V(D)J recombination by acting as a cofactor of the RAG complex: acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS). Proposed to be involved in the innate immune response to nucleic acids by acting as a promiscuous immunogenic DNA/RNA sensor which cooperates with subsequent discriminative sensing by specific pattern recognition receptors. In the extracellular compartment acts as a chemokine. Promotes proliferation and migration of endothelial cells implicating AGER/RAGE. Has antimicrobial activity in gastrointestinal epithelial tissues. Involved in inflammatory response to antigenic stimulus coupled with pro-inflammatory activity. Involved in modulation of neurogenesis probably by regulation of neural stem proliferation. Involved in articular cartilage surface maintenance implicating LEF1 and the Wnt/beta-catenin pathway.

Subunit / interactions. Interacts with POU2F2, POU2F1 and POU3F1. Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2. Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1. Directly interacts with SET. Interacts with LEF1.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Secreted.

Tissue specificity. Expressed in gastric and intestinal tissues (at protein level).

Post-translational modifications. Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys-106 and a possible intramolecular disulfide bond involving Cys-23 and Cys-45 give rise to different redox forms with specific functional activities in various cellular compartments: 1- fully reduced HMGB2 (HMGB2C23hC45hC106h), 2- disulfide HMGB2 (HMGB2C23-C45C106h) and 3- sulfonyl HMGB2 (HMGB2C23soC45soC106so). Acetylation enhances nucleosome binding and chromation remodeling activity.

Domain organisation. Both, HMG box 1 and HMG box 2, show antimicrobial activity.

Similarity. Belongs to the HMGB family.

RefSeq proteins (3): NP_001124160, NP_001124161, NP_002120* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR017967	HMG_boxA_CS	Conserved_site
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050342	HMGB	Family

Pfam: PF00505, PF09011

UniProt features (24 total): modified residue 11, compositionally biased region 5, region of interest 3, DNA-binding region 2, chain 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26583-F1	77.94	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (11): 3, 23, 30, 35, 43, 45, 90, 100, 106, 114, 141

Disulfide bonds (1): 23–45

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-140342	Apoptosis induced DNA fragmentation

MSigDB gene sets: 567 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CHROMOSOME_ORGANIZATION, FXR_IR1_Q6, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, REACTOME_APOPTOSIS_INDUCED_DNA_FRAGMENTATION, HORIUCHI_WTAP_TARGETS_DN, KANG_DOXORUBICIN_RESISTANCE_UP, GNF2_CENPF, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_MYELOID_CELL_HOMEOSTASIS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CELL_CHEMOTAXIS, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (40): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of endothelial cell proliferation (GO:0001938), inflammatory response to antigenic stimulus (GO:0002437), DNA topological change (GO:0006265), double-strand break repair via nonhomologous end joining (GO:0006303), chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), chromatin remodeling (GO:0006338), regulation of transcription by RNA polymerase II (GO:0006357), spermatid nucleus differentiation (GO:0007289), male gonad development (GO:0008584), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), negative regulation of gene expression (GO:0010629), DNA geometric change (GO:0032392), response to lipopolysaccharide (GO:0032496), positive regulation of interferon-beta production (GO:0032728), V(D)J recombination (GO:0033151), innate immune response (GO:0045087), positive regulation of innate immune response (GO:0045089), positive regulation of erythrocyte differentiation (GO:0045648), positive regulation of megakaryocyte differentiation (GO:0045654), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), response to steroid hormone (GO:0048545), regulation of neurogenesis (GO:0050767), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), cell chemotaxis (GO:0060326), cellular response to lipopolysaccharide (GO:0071222), regulation of stem cell proliferation (GO:0072091), negative regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902042), immune system process (GO:0002376), DNA recombination (GO:0006310), chemotaxis (GO:0006935), inflammatory response (GO:0006954), spermatogenesis (GO:0007283), positive regulation of gene expression (GO:0010628), positive chemotaxis (GO:0050918), regulation of hemopoiesis (GO:1903706)

GO Molecular Function (18): four-way junction DNA binding (GO:0000400), transcription cis-regulatory region binding (GO:0000976), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA binding (GO:0003677), damaged DNA binding (GO:0003684), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), transcription factor binding (GO:0008134), DNA binding, bending (GO:0008301), protein domain specific binding (GO:0019904), chemoattractant activity (GO:0042056), non-sequence-specific DNA binding, bending (GO:0044378), RAGE receptor binding (GO:0050786), supercoiled DNA binding (GO:0097100), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515)

GO Cellular Component (13): chromatin (GO:0000785), condensed chromosome (GO:0000793), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471), sperm annulus (GO:0097227), sperm principal piece (GO:0097228), extracellular region (GO:0005576), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Apoptotic execution phase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
DNA binding	4
transcription by RNA polymerase II	2
immune response	2
DNA conformation change	2
chromatin organization	2
nucleic acid binding	2
protein binding	2
chromosome	2
nuclear lumen	2
intracellular membraneless organelle	2
sperm flagellum	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
inflammatory response	1
DNA metabolic process	1
double-strand break repair	1
cellular component organization	1
nucleosome organization	1
protein-DNA complex assembly	1
regulation of DNA-templated transcription	1
nucleus organization	1
spermatid development	1
gonad development	1
development of primary male sexual characteristics	1
extrinsic apoptotic signaling pathway	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
somatic diversification of immune receptors via germline recombination within a single locus	1
defense response to symbiont	1

Protein interactions and networks

STRING

2432 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGB2	NUCLEOLIN	P19338	818
HMGB2	ANP32A	P39687	724
HMGB2	SYVN1	Q86TM6	681
HMGB2	BRF1	Q92994	654
HMGB2	SET	Q01105	553
HMGB2	ZNF687	Q8N1G0	549
HMGB2	SH3D19	Q5HYK7	548
HMGB2	NME1	P15531	502
HMGB2	YTHDF2	Q9Y5A9	497
HMGB2	YY1	P25490	494
HMGB2	NDUFS3	O75489	480
HMGB2	APEX1	P27695	479
HMGB2	DFFB	O76075	478
HMGB2	GZMA	P12544	476
HMGB2	IRF3	Q14653	453

IntAct

163 interactions, top by confidence:

A	B	Type	Score
HMGB2	MIEN1	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HMGB2	MIEN1	psi-mi:“MI:0914”(association)	0.710
HMGB2	ZNF428	psi-mi:“MI:0915”(physical association)	0.670
HMGB2	PKNOX1	psi-mi:“MI:0915”(physical association)	0.670
HMGB2	NOP53	psi-mi:“MI:0915”(physical association)	0.620
PKNOX1	HMGB2	psi-mi:“MI:0915”(physical association)	0.560
HMGB2	PKNOX1	psi-mi:“MI:0915”(physical association)	0.560
HMGB2	TSNAX	psi-mi:“MI:0915”(physical association)	0.560
HMGB2	ZNF668	psi-mi:“MI:0915”(physical association)	0.550
HMGB2	U2AF1	psi-mi:“MI:0915”(physical association)	0.550
HMGB2	COMMD1	psi-mi:“MI:0915”(physical association)	0.550
HMGB2	FLNA	psi-mi:“MI:0915”(physical association)	0.550
HMGB2	RPS28	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (358): PKNOX1 (Two-hybrid), HMGB2 (Affinity Capture-RNA), HMGB2 (Affinity Capture-RNA), HMGB2 (Affinity Capture-RNA), HMGB2 (Affinity Capture-MS), HMGB1 (Co-fractionation), HMGB2 (Co-fractionation), SUPT16H (Co-fractionation), HMGB2 (Affinity Capture-MS), HMGB2 (Proximity Label-MS), HMGB2 (Proximity Label-MS), HMGB2 (Affinity Capture-MS), HMGB2 (Affinity Capture-MS), HMGB2 (Affinity Capture-MS), HMGB2 (Affinity Capture-MS)

ESM2 similar proteins: A9RA84, B0CM99, B1MTB0, B2RPK0, O15347, O54879, P07156, P07746, P09429, P0CO24, P0CO25, P10103, P11873, P12682, P17741, P25979, P25980, P26583, P26584, P26586, P30681, P40618, P40620, P40621, P40622, P40623, P40625, P40626, P40632, P40644, P40673, P52925, P63158, P63159, P87057, Q05783, Q06943, Q07053, Q08IE6, Q09390

Diamond homologs: A9RA84, B0CM99, B1MTB0, B2RPK0, O01683, O04235, O15347, O15405, O49595, O49596, O49597, O54879, O64702, O94842, O94900, P07156, P07746, P09429, P0CO24, P0CO25, P10103, P11632, P11633, P11873, P12682, P17741, P23497, P26583, P26584, P26585, P26586, P27347, P30681, P40618, P40619, P40620, P40621, P40622, P40623, P40632

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
HMGB2	“up-regulates quantity by expression”	GFI1B	“transcriptional regulation”
HMGB2	“up-regulates activity”	POU2F2	binding
HMGB2	“up-regulates activity”	POU3F1	binding
HMGB2	“up-regulates activity”	POU2F1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 134 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TAK1-dependent IKK and NF-kappa-B activation	5	17.1×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

17 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

618 predictions. Top by Δscore:

Variant	Effect	Δscore
4:173332234:ATATC:A	acceptor_gain	1.0000
4:173332235:TATC:T	acceptor_gain	1.0000
4:173332236:ATC:A	acceptor_gain	1.0000
4:173332237:TC:T	acceptor_gain	1.0000
4:173332238:CC:C	acceptor_gain	1.0000
4:173332239:C:CC	acceptor_gain	1.0000
4:173332244:A:AC	acceptor_gain	1.0000
4:173332244:A:C	acceptor_gain	1.0000
4:173332246:A:C	acceptor_gain	1.0000
4:173332247:T:C	acceptor_gain	1.0000
4:173332247:T:TC	acceptor_gain	1.0000
4:173332251:C:CT	acceptor_gain	1.0000
4:173332252:A:T	acceptor_gain	1.0000
4:173332816:TGTA:T	donor_loss	1.0000
4:173332817:GTAC:G	donor_loss	1.0000
4:173332818:TAC:T	donor_loss	1.0000
4:173332820:CCTTT:C	donor_loss	1.0000
4:173332846:G:C	donor_gain	1.0000
4:173332991:CAGAT:C	acceptor_gain	1.0000
4:173332992:AGAT:A	acceptor_gain	1.0000
4:173332993:GAT:G	acceptor_gain	1.0000
4:173332994:AT:A	acceptor_gain	1.0000
4:173332995:TC:T	acceptor_loss	1.0000
4:173332996:C:CC	acceptor_gain	1.0000
4:173332997:T:G	acceptor_loss	1.0000
4:173333067:A:AC	donor_gain	1.0000
4:173333068:C:CC	donor_gain	1.0000
4:173333068:CG:C	donor_gain	1.0000
4:173333104:C:A	donor_gain	1.0000
4:173333145:C:CA	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000939790 (4:173333755 T>C), RS1002221210 (4:173333246 G>A), RS1002310680 (4:173331972 G>A), RS1002492482 (4:173333443 C>T), RS1002897949 (4:173334437 A>G), RS1003128550 (4:173335873 A>G), RS1003156451 (4:173334764 G>T), RS1003227564 (4:173331606 C>A), RS1004217634 (4:173335561 G>A), RS1004500269 (4:173335752 C>A), RS1004699199 (4:173331279 G>A), RS1005143584 (4:173331380 A>G), RS1005226861 (4:173334373 C>T), RS1006197127 (4:173333058 T>C), RS1006663497 (4:173333919 G>A)

Disease associations

OMIM: gene MIM:163906 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295734 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6832850	HMGB2		0.00	0
rs7686909	HMGB2		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.28	Kd	52.75	nM	CHEMBL5653589
7.28	ED50	52.75	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 11 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148519: Binding affinity to human HMGB2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0527	uM

CTD chemical–gene interactions

94 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
Estradiol	decreases expression, increases expression	4
Cyclosporine	affects expression, decreases expression, increases expression	4
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	3
Resveratrol	increases expression, decreases expression, affects cotreatment	3
Valproic Acid	decreases expression, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
perfluorooctanoic acid	decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Coumestrol	affects cotreatment, increases expression, affects reaction	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
Doxorubicin	affects expression, affects response to substance	2
Tretinoin	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
geraniol	decreases expression	1
quercitrin	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, increases reaction	1
zinc chromate	decreases expression, increases abundance	1
potassium nitrate	increases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
ochratoxin A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119024	Binding	Binding affinity to HMGB2 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

8 cell lines: 4 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2T2	SEES3-1V human HMGB2, clone1	Embryonic stem cell	Male
CVCL_A2T3	SEES3-1V human HMGB2, clone2	Embryonic stem cell	Male
CVCL_A2T4	SEES3-1V human HMGB2, clone3	Embryonic stem cell	Male
CVCL_B2YT	Abcam HEK293T HMGB2 KO	Transformed cell line	Female
CVCL_E0VP	Ubigene Huh-7 HMGB2 KO	Cancer cell line	Male
CVCL_F1SL	HyCyte NK-92 KO-hHMGB2	Cancer cell line	Male
CVCL_SR53	HAP1 HMGB2 (-) 1	Cancer cell line	Male
CVCL_SR54	HAP1 HMGB2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

11 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery