HMGA1

Summary

HMGA1 (high mobility group AT-hook 1, HGNC:5010) is a protein-coding gene on chromosome 6p21.31, encoding High mobility group protein HMG-I/HMG-Y (P17096). HMG-I/Y bind preferentially to the minor groove of A+T rich regions in double-stranded DNA. It is a common-essential gene (DepMap: required in 90.8% of cancer cell lines).

This gene encodes a chromatin-associated protein involved in the regulation of gene transcription, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells. The encoded protein preferentially binds to the minor groove of AT-rich regions in double-stranded DNA. Multiple transcript variants encoding different isoforms have been found for this gene. Pseudogenes of this gene have been identified on multiple chromosomes.

Source: NCBI Gene 3159 — RefSeq curated summary.

At a glance

• Gene–disease (curated): type 2 diabetes mellitus (Limited, GenCC)
• GWAS associations: 101
• Clinical variants (ClinVar): 19 total
• Phenotypes (HPO): 5
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 90.8% of screened cell lines (common-essential)
• Transcription factor: yes — 76 downstream targets (CollecTRI)
• MANE Select transcript: NM_145899

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5010
Approved symbol	HMGA1
Name	high mobility group AT-hook 1
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000137309
Ensembl biotype	protein_coding
OMIM	600701
Entrez	3159

Gene structure

Transcript identifiers

Ensembl transcripts: 67 — 66 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000311487, ENST00000347617, ENST00000374116, ENST00000401473, ENST00000447654, ENST00000478214, ENST00000674029, ENST00000703808, ENST00000703809, ENST00000873179, ENST00000873180, ENST00000873181, ENST00000873182, ENST00000873183, ENST00000873184, ENST00000873185, ENST00000873186, ENST00000873187, ENST00000873188, ENST00000873189, ENST00000873190, ENST00000873191, ENST00000873192, ENST00000873193, ENST00000873194, ENST00000873195, ENST00000924503, ENST00000924504, ENST00000924505, ENST00000924506, ENST00000924507, ENST00000924508, ENST00000924509, ENST00000924510, ENST00000924511, ENST00000924512, ENST00000924513, ENST00000924514, ENST00000924515, ENST00000924516, ENST00000924517, ENST00000924518, ENST00000924519, ENST00000924520, ENST00000924521, ENST00000924522, ENST00000924523, ENST00000924524, ENST00000924525, ENST00000924526, ENST00000924527, ENST00000924528, ENST00000924529, ENST00000924530, ENST00000924531, ENST00000924532, ENST00000924533, ENST00000924534, ENST00000924535, ENST00000924536, ENST00000924537, ENST00000924538, ENST00000924539, ENST00000963358, ENST00000963359, ENST00000963360, ENST00000963361

RefSeq mRNA: 12 — MANE Select: NM_145899 NM_001319077, NM_001319078, NM_001319079, NM_001319080, NM_001319081, NM_001319082, NM_002131, NM_145899, NM_145901, NM_145902, NM_145903, NM_145905

CCDS: CCDS4788, CCDS4789, CCDS93895

Canonical transcript exons

ENST00000311487 — 6 exons

Exon	Start	End
ENSE00001032854	34237204	34237317
ENSE00001160539	34244831	34246231
ENSE00001160563	34240737	34240915
ENSE00001269545	34236873	34236963
ENSE00003636652	34243468	34243518
ENSE00003664923	34242712	34242795

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 528.2985 / max 5809.6069, expressed in 1827 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67340	222.4408	1811
67339	186.8902	1822
67341	94.6007	1740
67342	17.6907	1750
67343	5.3302	1473
203965	1.3459	664

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.84	gold quality
esophagus mucosa	UBERON:0002469	98.04	gold quality
cartilage tissue	UBERON:0002418	97.96	gold quality
embryo	UBERON:0000922	97.84	gold quality
pharyngeal mucosa	UBERON:0000355	97.70	gold quality
cortical plate	UBERON:0005343	97.57	gold quality
ganglionic eminence	UBERON:0004023	97.25	gold quality
skin of abdomen	UBERON:0001416	96.86	gold quality
thymus	UBERON:0002370	96.76	gold quality
mucosa of transverse colon	UBERON:0004991	96.69	gold quality
skin of leg	UBERON:0001511	96.54	gold quality
nipple	UBERON:0002030	96.31	gold quality
vermiform appendix	UBERON:0001154	96.19	gold quality
endometrium epithelium	UBERON:0004811	95.82	gold quality
penis	UBERON:0000989	95.60	gold quality
right testis	UBERON:0004534	95.59	gold quality
zone of skin	UBERON:0000014	95.50	gold quality
left testis	UBERON:0004533	95.45	gold quality
gastrocnemius	UBERON:0001388	95.38	gold quality
upper arm skin	UBERON:0004263	95.38	gold quality
type B pancreatic cell	CL:0000169	95.35	silver quality
hindlimb stylopod muscle	UBERON:0004252	95.34	gold quality
lymph node	UBERON:0000029	95.30	gold quality
caecum	UBERON:0001153	95.22	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.05	gold quality
nasal cavity epithelium	UBERON:0005384	94.95	gold quality
stromal cell of endometrium	CL:0002255	94.86	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.67	gold quality
bone marrow cell	CL:0002092	94.53	gold quality
epithelium of esophagus	UBERON:0001976	94.43	gold quality

Single-cell (SCXA)

Detected in 40 experiment(s), a significant marker in 28.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	3656.57
E-CURD-79	yes	2470.99
E-MTAB-7407	yes	2146.26
E-GEOD-124263	yes	1977.65
E-MTAB-10855	yes	1584.05
E-GEOD-114530	yes	1238.90
E-MTAB-11121	yes	1215.67
E-GEOD-134144	yes	1148.53
E-MTAB-6701	yes	1128.76
E-CURD-122	yes	1126.16
E-MTAB-8142	yes	841.68
E-MTAB-10042	yes	807.45
E-HCAD-10	yes	799.55
E-CURD-98	yes	775.83
E-HCAD-32	yes	638.82

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

76 targets.

Target	Regulation
BAX
BCL2
BRCA1	Repression
BTK
CCNB2	Activation
CCND1
CCNE1	Repression
CD28
CD44	Activation
CDC25A	Activation
CDC6	Unknown
CDH1	Repression
CDKN1A
COL1A2
CRYAB	Unknown
CSF2	Activation
CXCL1	Unknown
CXCL12	Activation
CXCL14
CYBB
FCGRT
FGL1	Activation
FMNL2
GATA1	Unknown
GSTM1
H19
HAND1
HBB
HLA-DRA	Activation
HMGA1

JASPAR motifs

Motif	Name	Family
MA2124.1	Hmga1	HMGA

JASPAR matrix evidence (PMIDs): PMID:24062859

Upstream regulators (CollecTRI, top): CTNNB1, E2F1, HMGA1, MYC, POU2F1, POU2F2, SP1, TCF7L2

miRNA regulators (miRDB)

106 targeting HMGA1, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-1184	99.99	68.19	1458
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 90.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• HMG-I/Y is an oncogene important in the pathogenesis of human breast cancer (PMID:12002338)
• during apoptosis of different types of tumor cells there is a monomethylation of the nuclear protein HMGA1a (PMID:12653562)
• HMGI-Y physically interacts with Sp1 and C/EBP beta and facilitates the binding of both factors to the insulin receptor promoter (PMID:12665574)
• HMGA1a is methylated in leukemia cells induced to undergo apoptosis (PMID:12700639)
• HMGA1a expression was induced by hypoxia and accumulated in nuclear speckles with the endogenous splicing factor SC35. Overexpression of HMGA1a generated Presenilin-2V. (PMID:12761578)
• expression and localization of HMGI(Y) in the subpopulations of placental tissue (PMID:13680222)
• HMGA1 cooperates with either the N- or the C-terminal transcriptional activation domain of the estrogen receptor to stimulate estrogen response element binding and promoter transcriptional activity (PMID:14960313)
• regulated dynamic properties of HMGA1a fusion proteins indicate that HMGA1 proteins are mechanistically involved in local and global changes in chromatin structure (PMID:15213251)
• HMG-I(Y) expression may have a role in intrahepatic metastasis of hepatocellular carcinoma (PMID:15247513)
• Examination of HMGA1a posttranslational modification patterns in breast cancer cell lines supports the existence of a dynamic biochemical switching mechanism for HMGA1a expressed in different ways in normal and malignant cells. (PMID:15350136)
• HMGA1 positively regulates the human KL promoter in breast and ovarian cancer cells (PMID:15378028)
• HMGA1 expression might have a role in human breast cancer (PMID:15569996)
• study focuses on whether HMGA1a and HMGA1b proteins isolated from the same cell type have identical or different post-translational modifications patterns and whether these isoform patterns differ between non-malignant and malignant cells (PMID:15591590)
• These results suggest hypoxia-induced signals in SK-N-SH cells lead to expression of HMGA1a, which may induce expression of the transcription factor N-Myc. (PMID:15631895)
• sites of phosphorylation and the nature of methylation of HMGA1 (PMID:15835918)
• HMGA1 is translocated from the nucleus into the cytoplasm and mitochondria and associates with the regulatory D-loop region of the mitochondrial genome. (PMID:15893306)
• HMGA1 as one of the first mediators in the development of human atherosclerotic plaques (PMID:15901130)
• HMGA1 directly influences both the formation and repair of UV-induced DNA lesions in intact cells (PMID:16033759)
• HMGA1 repression by RNA interference reduced neuroblastoma cell proliferation, indicating that HMGA1 is a novel MYCN target gene relevant for neuroblastoma tumorigenesis. (PMID:16166307)
• NF-Y and HMG-I(Y) may play an important role in regulating the IL-10 promoter activity in B cells. (PMID:16256199)
• mtDNA levels were reduced approximately 2-fold in HMGA1a over-expressing transgenic MCF-7 cells (PMID:17045586)
• Since HMGA1 regulates IR promoter activity, expression of IR gene was impaired causing reduction of IR on cell surface and that compromises with insulin sensitivity. (PMID:17434141)
• Our results suggest that PRMT1 might be involved in the previously reported methylation of Arg25 in HMGA1a in vivo. (PMID:17550233)
• HMGA1 proteins are involved in inhibiting XPA expression, resulting in increased UV sensitivity in cells that overexpress these proteins (PMID:17616660)
• Fluorescence in situ hybridization was used to identify rearrangements of HMGA2 and its homologue HMGA1. HMGA1 rearrangement was not found in any of the cases (PMID:17654722)
• HMGA1 nonhistone chromatin proteins, the SWI/SNF chromatin remodeling complexes, and sequence-specific transcription factors act together to regulate the expression of the CRYAB gene. (PMID:17723105)
• HMGA1 disturbs retobblastoma protein (RB)-mediated cell arrest, suggesting a negative control of RB by HMGA1. (PMID:17877762)
• HMGA1a is a sequence-specific RNA-binding factor causing sporadic Alzheimer’s disease-linked exon skipping of presenilin-2 pre-mRNA (PMID:17903177)
• the different profiles of HMGA1 protein expression in post-pubertal testicular tumours could represent a valuable diagnostic tool in some cases in which the histological differential diagnosis is problematic (PMID:17935122)
• HMGA proteins are overexpressed in different tumors and the HMGA genes are often involved in chromosomal rearrangements [review] (PMID:18202751)
• A previously unknown role for HMGA1 in the regulation of hNOS2, is demonstrated. (PMID:18279675)
• HMGA1 overexpression is associated with pancreatic adenocarcinoma and promoted chemoresistance to gemcitabine (PMID:18316571)
• HMGA1 promotes tumorigenicity through a PI3-K/Akt-dependent mechanism (PMID:18473350)
• HMGA1 expression is necessary for the full expression of HPV18 E6 and E7 oncoproteins thus establishing a positive autoregulatory loop between HPV E6/E7 and HMGA1 expression. (PMID:18670638)
• HMGA1 proteins bind directly to Hand1 promoter both in vitro and in vivo and inhibit Hand1 promoter activity (PMID:19060921)
• In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. (PMID:19074878)
• MiR-16 negatively regulate HMGA1 and caprin-1 which are involved in cell proliferation. (PMID:19250063)
• The HMGI-C and HMGI(Y) quantitations by real-time RT-PCR are associated with Dukes staging and metastasis; hence, the gene expression levels may be useful in clinical practice. (PMID:19609535)
• Increased ROS levels and reduced repair efficiency in HMGA1-overexpressing cells likely contribute to the increased occurrence of mutations in mtDNA frequently observed in cancer cells. (PMID:19687300)
• HMGA1 is involved in proliferation and gastric tumor formation via the Wnt/beta-catenin pathway. (PMID:19729480)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-161c3.6	ENSDARG00000078781
mus_musculus	Hmga1b	ENSMUSG00000078249
rattus_norvegicus	Hmga1	ENSRNOG00000000488

Protein

Protein identifiers

High mobility group protein HMG-I/HMG-Y — P17096 (reviewed: P17096)

Alternative names: High mobility group AT-hook protein 1, High mobility group protein R

All UniProt accessions (5): P17096, A0A669KAX1, A0A994J434, A0A994J705, Q5T6U8

UniProt curated annotations — full annotation on UniProt →

Function. HMG-I/Y bind preferentially to the minor groove of A+T rich regions in double-stranded DNA. It is suggested that these proteins could function in nucleosome phasing and in the 3’-end processing of mRNA transcripts. They are also involved in the transcription regulation of genes containing, or in close proximity to A+T-rich regions.

Subunit / interactions. Interacts with HIPK2.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Constitutively phosphorylated on two or three sites. Hyperphosphorylated at early stages of apoptosis, followed by dephosphorylation and methylation, which coincides with chromatin condensation. Isoforms HMG-I and HMG-Y can be phosphorylated by HIPK2. Phosphorylation of HMG-I at Ser-36, Thr-53 and Thr-78 and of HMG-Y at Thr-42 and Thr-67 by HIPK2 modulates DNA-binding affinity. HMG-Y is not methylated. Methylation at Arg-58 is mutually exclusive with methylation at Arg-60.

Disease relevance. A chromosomal aberration involving HMGA1 is found in pulmonary chondroid hamartoma. Translocation t(6;14)(p21;q23-24) with RAD51B.

Similarity. Belongs to the HMGA family.

Isoforms (3)

UniProt ID	Names	Canonical?
P17096-1	HMG-I, HMGA1a	yes
P17096-2	HMG-Y, HMGA1b
P17096-3	HMG-R, HMGA1c

RefSeq proteins (12): NP_001306006, NP_001306007, NP_001306008, NP_001306009, NP_001306010, NP_001306011, NP_002122, NP_665906, NP_665908, NP_665909, NP_665910, NP_665912 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000116	HMGA	Family
IPR000637	HMGI/Y_DNA-bd_CS	Conserved_site
IPR017956	AT_hook_DNA-bd_motif	Conserved_site

UniProt features (42 total): modified residue 24, DNA-binding region 3, mutagenesis site 3, compositionally biased region 3, splice variant 2, region of interest 2, initiator methionine 1, chain 1, cross-link 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8CPG	X-RAY DIFFRACTION	1.4
2EZD	SOLUTION NMR
2EZE	SOLUTION NMR
2EZF	SOLUTION NMR
2EZG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17096-F1	65.28	0.00

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 (25): 2, 7, 8, 9, 9, 15, 26, 26, 26, 36, 39, 44, 49, 53, 58, 58, 60, 60, 78, 99 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
26	does not affect methylation by prmt6.
58	decreases methylation by prmt6. abolishes methylation by prmt6; when associated with a-60.
60	decreases methylation by prmt6. abolishes methylation by prmt6; when associated with a-58.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-162592	Integration of provirus
R-HSA-164843	2-LTR circle formation
R-HSA-175567	Integration of viral DNA into host genomic DNA
R-HSA-177539	Autointegration results in viral DNA circles
R-HSA-180689	APOBEC3G mediated resistance to HIV-1 infection
R-HSA-180910	Vpr-mediated nuclear import of PICs
R-HSA-2559584	Formation of Senescence-Associated Heterochromatin Foci (SAHF)

MSigDB gene sets: 433 (showing top): E2F_Q4_01, SHEPARD_BMYB_MORPHOLINO_UP, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, HORIUCHI_WTAP_TARGETS_DN, GOMF_ENDONUCLEASE_ACTIVITY, REACTOME_INTERACTIONS_OF_VPR_WITH_HOST_CELLULAR_PROTEINS, ACTACCT_MIR196A_MIR196B, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, REACTOME_INTEGRATION_OF_PROVIRUS, E2F4DP1_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOMF_NUCLEASE_ACTIVITY, CROONQUIST_NRAS_SIGNALING_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP

GO Biological Process (11): base-excision repair (GO:0006284), nucleosome disassembly (GO:0006337), regulation of DNA-templated transcription (GO:0006355), negative regulation of cell population proliferation (GO:0008285), intracellular signal transduction (GO:0035556), 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), oncogene-induced cell senescence (GO:0090402), regulation of gene expression (GO:0010468), positive regulation of macromolecule biosynthetic process (GO:0010557)

GO Molecular Function (20): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), cis-regulatory region sequence-specific DNA binding (GO:0000987), transcription coregulator binding (GO:0001221), DNA binding (GO:0003677), minor groove of adenine-thymine-rich DNA binding (GO:0003680), chromatin binding (GO:0003682), transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0003906), DNA binding, bending (GO:0008301), enzyme binding (GO:0019899), structural constituent of chromatin (GO:0030527), nuclear retinoic acid receptor binding (GO:0042974), peroxisome proliferator activated receptor binding (GO:0042975), nuclear retinoid X receptor binding (GO:0046965), 5’-deoxyribose-5-phosphate lyase activity (GO:0051575), molecular adaptor activity (GO:0060090), molecular function activator activity (GO:0140677), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytosol (GO:0005829), focal adhesion (GO:0005925), nuclear membrane (GO:0031965), senescence-associated heterochromatin focus (GO:0035985), RNA polymerase II transcription regulator complex (GO:0090575), chromatin (GO:0000785), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Integration of provirus	3
Early Phase of HIV Life Cycle	1
Host Interactions of HIV factors	1
Interactions of Vpr with host cellular proteins	1
DNA Damage/Telomere Stress Induced Senescence	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	3
binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
positive regulation of DNA-templated transcription	2
regulation of macromolecule biosynthetic process	2
nucleic acid binding	2
DNA repair	1
protein-DNA complex disassembly	1
nucleosome organization	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
intracellular anatomical structure	1
signal transduction	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cellular senescence	1
gene expression	1
macromolecule biosynthetic process	1
positive regulation of biosynthetic process	1
positive regulation of macromolecule metabolic process	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
transcription factor binding	1
DNA secondary structure binding	1
transcription regulator activity	1
transcription coregulator activity	1
DNA endonuclease activity	1
DNA binding	1
protein binding	1
chromatin	1
structural molecule activity	1
nuclear receptor binding	1
signaling receptor binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

133 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
HMGA1	H2AC21	psi-mi:“MI:0915”(physical association)	0.670
HMGA1	H2AC21	psi-mi:“MI:0914”(association)	0.670
HMGA1	ORC6	psi-mi:“MI:0915”(physical association)	0.600
HMGA1	ORC6	psi-mi:“MI:0407”(direct interaction)	0.600
ORC6	HMGA1	psi-mi:“MI:0915”(physical association)	0.600
H1-3	HMGA1	psi-mi:“MI:0915”(physical association)	0.560
H4C16	HMGA1	psi-mi:“MI:0915”(physical association)	0.560
H2BC21	HMGA1	psi-mi:“MI:0915”(physical association)	0.560
NSD1	HMGA1	psi-mi:“MI:0915”(physical association)	0.560
SP1	HMGA1	psi-mi:“MI:0915”(physical association)	0.540
HMGA1	CEBPB	psi-mi:“MI:0915”(physical association)	0.540
HMGA1	SP1	psi-mi:“MI:0407”(direct interaction)	0.540
CEBPB	HMGA1	psi-mi:“MI:0407”(direct interaction)	0.540
HMGA1	MACROH2A1	psi-mi:“MI:0914”(association)	0.530
	HMGA1	psi-mi:“MI:0914”(association)	0.520
HMGA1		psi-mi:“MI:0407”(direct interaction)	0.520
HMGA1		psi-mi:“MI:0407”(direct interaction)	0.440
HMGA1	ORC1	psi-mi:“MI:0407”(direct interaction)	0.410
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
ORC2	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
HMGA1	PRXL2A	psi-mi:“MI:0915”(physical association)	0.400
NOP14	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
ELP2	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
KCND1	HMGA1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (545): HMGA1 (Affinity Capture-Western), PPARG (Affinity Capture-Western), HMGA1 (Affinity Capture-Western), HMGA1 (Affinity Capture-MS), HMGA1 (Affinity Capture-MS), HMGA1 (Two-hybrid), HMGA1 (Reconstituted Complex), HMGA1 (Biochemical Activity), HMGA1 (Affinity Capture-MS), HMGA1 (Affinity Capture-MS), HMGA1 (Affinity Capture-MS), HMGA1 (Affinity Capture-MS), HMGA1 (Affinity Capture-MS), HMGA1 (Affinity Capture-MS), HMGA1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K0D3, A0A1L8GR68, A0JPP1, B5DF11, D3ZTQ1, O88878, P17095, P17096, P28667, P29536, P35566, P49006, P51608, P52926, P52927, P84798, Q00566, Q0VBZ9, Q15004, Q15054, Q3USH5, Q3UZA1, Q3ZBT0, Q5BK20, Q5EG55, Q5XG50, Q5ZK28, Q60974, Q69Z61, Q6DGQ4, Q6JBY9, Q6PGH2, Q6URC2, Q86XZ4, Q86YP4, Q8BVA4, Q8CHY6, Q8K1N4, Q8K585, Q8N228

Diamond homologs: P17095, P17096, Q6URC2, Q8K585, Q9QXP3

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	HMGA1	phosphorylation
CDK2	down-regulates	HMGA1	phosphorylation
HIPK2	down-regulates	HMGA1	phosphorylation
HMGA1	“up-regulates activity”	POU3F1	binding
HMGA1	“up-regulates quantity by expression”	KITLG	“transcriptional regulation”
HMGA1	“up-regulates quantity by expression”	SLC2A3	“transcriptional regulation”
CAV1	“up-regulates activity”	HMGA1	relocalization
ATM	“up-regulates activity”	HMGA1	phosphorylation
PRKCD	down-regulates	HMGA1	phosphorylation
CSNK2A1	unknown	HMGA1	phosphorylation
CSNK2A2	unknown	HMGA1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 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
Assembly of the ORC complex at the origin of replication	10	18.2×	1e-07
FXIIa activates plasma kallikrein-kinin system	8	15.2×	1e-05
Packaging Of Telomere Ends	6	14.5×	8e-05
RNA Polymerase I Promoter Opening	7	14.2×	3e-05
ChAHP complex assembly	7	14.2×	3e-05
Condensation of Prophase Chromosomes	8	13.8×	2e-05
DNA methylation	7	13.7×	3e-05
Recognition and association of DNA glycosylase with site containing an affected purine	6	13.4×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
heterochromatin formation	6	12.9×	2e-03
nucleosome assembly	10	11.8×	1e-05
chromatin organization	10	8.3×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

967 predictions. Top by Δscore:

Variant	Effect	Δscore
6:34239111:TCTCC:T	donor_gain	1.0000
6:34240735:A:AG	acceptor_gain	1.0000
6:34240736:G:GG	acceptor_gain	1.0000
6:34240736:GC:G	acceptor_gain	1.0000
6:34240736:GCA:G	acceptor_gain	1.0000
6:34240736:GCAT:G	acceptor_gain	1.0000
6:34242710:A:AG	acceptor_gain	1.0000
6:34242710:AGAAG:A	acceptor_gain	1.0000
6:34242711:G:GA	acceptor_gain	1.0000
6:34242711:GA:G	acceptor_gain	1.0000
6:34242711:GAA:G	acceptor_gain	1.0000
6:34242711:GAAGG:G	acceptor_gain	1.0000
6:34242764:G:GT	donor_gain	1.0000
6:34242764:G:T	donor_gain	1.0000
6:34242792:CCGGG:C	donor_loss	1.0000
6:34242793:CGGGT:C	donor_loss	1.0000
6:34242794:GGGTG:G	donor_loss	1.0000
6:34242795:GGTG:G	donor_loss	1.0000
6:34242796:G:GG	donor_gain	1.0000
6:34242797:T:A	donor_loss	1.0000
6:34236962:GC:G	donor_gain	0.9900
6:34236964:G:GG	donor_gain	0.9900
6:34237314:CGCGG:C	donor_loss	0.9900
6:34237315:GCG:G	donor_gain	0.9900
6:34237315:GCGGT:G	donor_loss	0.9900
6:34237316:CGG:C	donor_loss	0.9900
6:34237317:GGTG:G	donor_loss	0.9900
6:34237318:G:C	donor_loss	0.9900
6:34237318:G:GG	donor_gain	0.9900
6:34237319:TGA:T	donor_loss	0.9900

AlphaMissense

680 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:34240863:G:T	R28M	0.999
6:34240860:G:A	G27D	0.998
6:34240863:G:C	R28T	0.998
6:34240864:G:C	R28S	0.998
6:34240864:G:T	R28S	0.998
6:34240859:G:C	G27R	0.997
6:34242744:A:C	R56S	0.997
6:34242744:A:T	R56S	0.997
6:34242751:G:C	G59R	0.997
6:34242752:G:A	G59D	0.997
6:34242763:G:A	G63R	0.997
6:34242763:G:C	G63R	0.997
6:34242764:G:A	G63E	0.997
6:34242757:C:T	P61S	0.995
6:34243506:A:C	R86S	0.995
6:34243506:A:T	R86S	0.995
6:34240859:G:T	G27C	0.994
6:34240860:G:T	G27V	0.994
6:34240873:G:C	K31N	0.994
6:34240873:G:T	K31N	0.994
6:34242743:G:C	R56T	0.993
6:34242751:G:T	G59C	0.993
6:34242752:G:T	G59V	0.993
6:34240868:C:A	R30S	0.992
6:34240871:A:G	K31E	0.992
6:34242741:G:C	K55N	0.992
6:34242741:G:T	K55N	0.992
6:34242758:C:A	P61Q	0.992
6:34242762:G:C	K62N	0.992
6:34242762:G:T	K62N	0.992

dbSNP variants (sampled 300 via entrez): RS1000055979 (6:34236150 G>A), RS1000097676 (6:34239965 C>A,G), RS1000159077 (6:34236368 C>CA), RS1000396258 (6:34246423 A>G), RS1000947920 (6:34236759 G>A), RS1001055916 (6:34238801 A>T), RS1001086760 (6:34236700 A>C), RS1001088458 (6:34239013 G>C), RS1001152414 (6:34244463 C>T), RS1001264917 (6:34241206 T>G), RS1001290382 (6:34237454 AGCCGGCGGCGGGG>A), RS1001409794 (6:34235761 G>A), RS1001422427 (6:34235589 A>C), RS1001602667 (6:34239558 T>G), RS1001859210 (6:34244834 A>C,G)

Disease associations

OMIM: gene MIM:600701 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
type 2 diabetes mellitus	Limited	Autosomal dominant

Mondo (1): type 2 diabetes mellitus (MONDO:0005148)

Orphanet (0):

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000855	Insulin resistance
HP:0003584	Late onset
HP:0005978	Type II diabetes mellitus
HP:0031819	Increased waist to hip ratio

GWAS associations

101 associations (top):

Study	Trait	p-value
GCST000175_38	Height	1.000000e-08
GCST000372_16	Height	8.000000e-11
GCST000380_1	Height	3.000000e-08
GCST000522_11	Height	2.000000e-08
GCST000611_17	Height	1.000000e-13
GCST000644_8	Height	7.000000e-06
GCST000817_25	Height	3.000000e-08
GCST000817_3	Height	6.000000e-12
GCST000817_63	Height	8.000000e-28
GCST000830_21	Body mass index	3.000000e-08
GCST001263_7	Height	2.000000e-08
GCST001956_72	Height	5.000000e-15
GCST002647_138	Height	2.000000e-49
GCST002702_55	Height	2.000000e-29
GCST002782_246	Waist-to-hip ratio adjusted for body mass index	7.000000e-09
GCST002782_247	Waist-to-hip ratio adjusted for body mass index	2.000000e-07
GCST003995_33	Tonsillectomy	4.000000e-08
GCST004063_125	Waist circumference adjusted for body mass index	2.000000e-16
GCST004063_126	Waist circumference adjusted for body mass index	6.000000e-20
GCST004063_127	Waist circumference adjusted for body mass index	8.000000e-07
GCST004067_171	Hip circumference adjusted for BMI	2.000000e-06
GCST004067_67	Hip circumference adjusted for BMI	9.000000e-09
GCST004500_24	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	7.000000e-17
GCST004500_75	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	7.000000e-06
GCST004500_86	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	6.000000e-15
GCST004501_63	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	2.000000e-16
GCST004501_86	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	1.000000e-13
GCST004504_59	Waist circumference adjusted for BMI in non-smokers	6.000000e-12
GCST004504_60	Waist circumference adjusted for BMI in non-smokers	2.000000e-14
GCST004562_129	Waist circumference adjusted for body mass index	8.000000e-11

EFO canonical traits (26, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007924	tonsillectomy risk measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004344	birth weight
EFO:0006941	grip strength measurement
EFO:0009592	social interaction measurement
EFO:0006335	systolic blood pressure
EFO:0004312	vital capacity
EFO:0004314	forced expiratory volume
EFO:0004324	body weights and measures
EFO:0005939	parental genotype effect measurement
EFO:0000195	metabolic syndrome
EFO:0004509	hemoglobin measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004530	triglyceride measurement
EFO:0004338	body weight
EFO:0004980	appendicular lean mass
EFO:0004251	myeloproliferative disorder
EFO:0004587	lymphocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0007985	platelet crit

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724678 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment	4
sodium arsenite	affects cotreatment, increases expression, decreases expression, increases abundance	4
Air Pollutants	increases abundance, increases expression, affects cotreatment	3
Ethanol	decreases reaction, increases expression, affects reaction, increases secretion, decreases expression (+1 more)	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression	3
perfluorooctanoic acid	increases activity, decreases expression	2
epigallocatechin gallate	affects cotreatment, increases expression, decreases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
pterostilbene	increases secretion, decreases expression, increases reaction, decreases reaction, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Caffeine	affects phosphorylation, decreases expression	2
Estradiol	decreases expression, decreases reaction, increases expression, affects cotreatment	2
Formaldehyde	decreases expression	2
Progesterone	affects cotreatment, decreases expression, decreases reaction	2
Quercetin	increases expression, decreases phosphorylation	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
Cyclosporine	increases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
tert-Butylhydroperoxide	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
4-(2-aminoethyl)benzenesulfonylfluoride	affects cotreatment, decreases expression, decreases reaction	1
2,4,6-tribromophenol	decreases expression	1
methyleugenol	increases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697688	Binding	Inhibition of HMGA1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2S3	SEES3-1V human HMGA1, clone1	Embryonic stem cell	Male
CVCL_A2S4	SEES3-1V human HMGA1, clone2	Embryonic stem cell	Male
CVCL_A2S5	SEES3-1V human HMGA1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus