HEXIM2

Summary

HEXIM2 (HEXIM P-TEFb complex subunit 2, HGNC:28591) is a protein-coding gene on chromosome 17q21.31, encoding Protein HEXIM2 (Q96MH2). Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor.

This gene encodes a member of the HEXIM family of proteins. This protein is a component of the 7SK small nuclear ribonucleoprotein. This protein has been found to negatively regulate the kinase activity of the cyclin-dependent kinase P-TEFb, which phosphorylates multiple target proteins to promote transcriptional elongation. This gene is located approximately 7 kb downstream from related family member HEXIM1 on chromosome 17. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 124790 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 46 total
• MANE Select transcript: NM_001303441

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28591
Approved symbol	HEXIM2
Name	HEXIM P-TEFb complex subunit 2
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32384
Ensembl gene	ENSG00000168517
Ensembl biotype	protein_coding
OMIM	615695
Entrez	124790

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 32 protein_coding

ENST00000307275, ENST00000585340, ENST00000586681, ENST00000589230, ENST00000591070, ENST00000591576, ENST00000592695, ENST00000593138, ENST00000894989, ENST00000894990, ENST00000894991, ENST00000894992, ENST00000894993, ENST00000894994, ENST00000894995, ENST00000894996, ENST00000894997, ENST00000894998, ENST00000894999, ENST00000895000, ENST00000895001, ENST00000895002, ENST00000895003, ENST00000895004, ENST00000895005, ENST00000895006, ENST00000928699, ENST00000928700, ENST00000963067, ENST00000963068, ENST00000963069, ENST00000963070

RefSeq mRNA: 10 — MANE Select: NM_001303441 NM_001303436, NM_001303437, NM_001303438, NM_001303439, NM_001303440, NM_001303441, NM_001303442, NM_001303443, NM_001303444, NM_144608

CCDS: CCDS11496

Canonical transcript exons

ENST00000589230 — 4 exons

Exon	Start	End
ENSE00001134308	45162488	45162635
ENSE00002860243	45169015	45170035
ENSE00002929486	45161875	45162031
ENSE00003639836	45162750	45162859

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 92.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.5284 / max 54.2742, expressed in 1646 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161246	4.4822	1554
161243	0.6206	341
161244	0.1735	69
161247	0.0714	19
161248	0.0623	19
161245	0.0619	11
161249	0.0566	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	92.07	gold quality
left testis	UBERON:0004533	91.40	gold quality
muscle of leg	UBERON:0001383	91.17	gold quality
right testis	UBERON:0004534	91.12	gold quality
testis	UBERON:0000473	89.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.46	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.64	gold quality
pancreatic ductal cell	CL:0002079	85.31	silver quality
right uterine tube	UBERON:0001302	84.57	gold quality
sural nerve	UBERON:0015488	84.40	gold quality
apex of heart	UBERON:0002098	84.39	gold quality
right lobe of liver	UBERON:0001114	84.29	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.33	gold quality
skeletal muscle tissue	UBERON:0001134	83.32	gold quality
right adrenal gland	UBERON:0001233	82.86	gold quality
sperm	CL:0000019	82.69	silver quality
prefrontal cortex	UBERON:0000451	82.64	gold quality
right adrenal gland cortex	UBERON:0035827	82.40	gold quality
monocyte	CL:0000576	82.37	gold quality
leukocyte	CL:0000738	82.13	gold quality
biceps brachii	UBERON:0001507	81.53	gold quality
left adrenal gland cortex	UBERON:0035825	81.52	gold quality
granulocyte	CL:0000094	81.51	gold quality
left adrenal gland	UBERON:0001234	81.33	gold quality
tendon of biceps brachii	UBERON:0008188	81.04	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	80.97	silver quality
tibialis anterior	UBERON:0001385	80.86	silver quality
body of pancreas	UBERON:0001150	80.77	gold quality
metanephros cortex	UBERON:0010533	80.37	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting HEXIM2, 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-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-555	95.92	65.25	564

Literature-anchored findings (GeneRIF, showing 5)

• HEXIM2 can functionally and quantitatively compensate for the loss of HEXIM1 (PMID:15713661)
• utilization of HEXIM1 or HEXIM2 to bind and inhibit P-TEFb can be differentially regulated in vivo. (PMID:15713662)
• Positive transcription elongation factor b regulates eukaryotic gene expression at the level of elongation and is controlled by the reversible association with HEXIM2. (PMID:15965233)
• The tripartite protein-RNA complex formation between Hexim, Cyclin T and 7SK snRNA, was analyzed. (PMID:19883659)
• Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy. (PMID:38816355)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hexim1	ENSDARG00000036482
mus_musculus	Hexim2	ENSMUSG00000043372
rattus_norvegicus	Hexim2	ENSRNOG00000021287
drosophila_melanogaster	Hexim	FBGN0038251

Paralogs (1): HEXIM1 (ENSG00000186834)

Protein

Protein identifiers

Protein HEXIM2 — Q96MH2 (reviewed: Q96MH2)

Alternative names: Hexamethylene bis-acetamide-inducible protein 2

All UniProt accessions (6): Q96MH2, K7EIM4, K7EJA3, K7ELS4, K7ERG7, K7ESM2

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor. Core component of the 7SK RNP complex: in cooperation with 7SK snRNA sequesters P-TEFb in a large inactive 7SK snRNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation.

Subunit / interactions. Homooligomer and heterooligomer with HEXIM1; probably dimeric. Core component of the 7SK RNP complex, at least composed of 7SK RNA, LARP7, MEPCE, HEXIM1 (or HEXIM2) and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1). Interacts with CCNT2.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed with higher expression in testis. HEXIM1 and HEXIM2 are differentially expressed.

Domain organisation. The coiled-coil domain mediates oligomerization.

Induction. Up-regulated by HMBA (hexamethylene bisacetamide) (at protein level).

Similarity. Belongs to the HEXIM family.

RefSeq proteins (10): NP_001290365, NP_001290366, NP_001290367, NP_001290368, NP_001290369, NP_001290370, NP_001290371, NP_001290372, NP_001290373, NP_653209 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024872	HEXIM	Family

Pfam: PF15313

UniProt features (21 total): modified residue 9, compositionally biased region 5, region of interest 3, mutagenesis site 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96MH2-F1	72.34	0.35

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 (9): 29, 32, 39, 46, 51, 53, 71, 76, 81

Mutagenesis-validated functional residues (2):

Position	Phenotype
143	loss of interaction with p-tefb.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 154 (showing top): RNGTGGGC_UNKNOWN, PAX4_01, TGCGCANK_UNKNOWN, GOBP_CELL_CYCLE_PHASE_TRANSITION, TAL1ALPHAE47_01, HNF1_Q6, AAAYRNCTG_UNKNOWN, CEBPB_01, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, WTGAAAT_UNKNOWN, ZIC1_01, GOBP_NEGATIVE_REGULATION_OF_MITOTIC_CELL_CYCLE

GO Biological Process (3): negative regulation of transcription by RNA polymerase II (GO:0000122), negative regulation of G2/M transition of mitotic cell cycle (GO:0010972), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (5): cyclin-dependent protein serine/threonine kinase inhibitor activity (GO:0004861), snRNA binding (GO:0017069), identical protein binding (GO:0042802), 7SK snRNA binding (GO:0097322), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
G2/M transition of mitotic cell cycle	1
regulation of G2/M transition of mitotic cell cycle	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G2/M phase transition	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
cyclin-dependent protein serine/threonine kinase activity	1
cyclin-dependent protein serine/threonine kinase regulator activity	1
protein serine/threonine kinase inhibitor activity	1
RNA binding	1
protein binding	1
snRNA binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEXIM2	LARP7	Q4G0J3	997
HEXIM2	MEPCE	Q7L2J0	997
HEXIM2	HEXIM1	O94992	968
HEXIM2	CCNT1	O60563	845
HEXIM2	CDK9	P50750	842
HEXIM2	BRD4	O60885	707
HEXIM2	AFF1	P51825	635
HEXIM2	CCNT2	O60583	633
HEXIM2	METTL8	Q9H825	616
HEXIM2	TLCD4	Q96MV1	562
HEXIM2	AFF4	Q9UHB7	552
HEXIM2	ELL2	O00472	524
HEXIM2	RBM8A	Q9Y5S9	506
HEXIM2	SUPT5H	O00267	468
HEXIM2	GFI1B	Q5VTD9	464

IntAct

196 interactions, top by confidence:

A	B	Type	Score
CDK9	CCNT1	psi-mi:“MI:0914”(association)	0.980
JUNB	FOS	psi-mi:“MI:0914”(association)	0.950
HEXIM1	CCNT1	psi-mi:“MI:0914”(association)	0.930
LARP7	CCNT1	psi-mi:“MI:0914”(association)	0.850
HEXIM1	HEXIM2	psi-mi:“MI:0915”(physical association)	0.800
TCF12	HEXIM2	psi-mi:“MI:0915”(physical association)	0.740
HEXIM2	TCF12	psi-mi:“MI:0915”(physical association)	0.740
HEXIM2	HEXIM2	psi-mi:“MI:0915”(physical association)	0.740
HEXIM2	AHCYL1	psi-mi:“MI:0914”(association)	0.740
AHCYL1	HEXIM2	psi-mi:“MI:0915”(physical association)	0.740
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
PIN1	HEXIM2	psi-mi:“MI:0915”(physical association)	0.720
HEXIM2	PIN1	psi-mi:“MI:0915”(physical association)	0.720
HEXIM2	PRDM14	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (136): HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), HEXIM2 (Two-hybrid), CCDC36 (Two-hybrid), HEXIM2 (Affinity Capture-MS), HEXIM2 (Affinity Capture-MS), HEXIM2 (Two-hybrid)

ESM2 similar proteins: A0A8I5KY20, A2A9T0, A2IDD5, B0BNK9, B8ZZ34, C9JI98, C9JLR9, F5GYI3, O18734, P0CG25, P84157, Q0IIA6, Q0PHV7, Q0X0E2, Q13387, Q1RMK9, Q2M3D2, Q2TAM9, Q3ZCQ3, Q4VA45, Q673H1, Q69YZ2, Q6NS60, Q6P6N5, Q6PJ61, Q7Z6J2, Q80ZJ8, Q810I0, Q86SX3, Q86UD0, Q86XT2, Q8BNN1, Q8IUW3, Q8N4Y2, Q8N6N2, Q8QZV0, Q8R4T5, Q8TF61, Q8VCR9, Q8WXF8

Diamond homologs: A5D8S8, O94992, Q0X0C4, Q0X0E2, Q3TVI4, Q4V7W3, Q5M9G1, Q8R409, Q96MH2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 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
Transcription of the HIV genome	5	14.9×	6e-03
RNA Polymerase II Pre-transcription Events	5	11.9×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of transforming growth factor beta receptor signaling pathway	5	11.6×	5e-03
transcription by RNA polymerase II	8	7.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

827 predictions. Top by Δscore:

Variant	Effect	Δscore
17:45162856:CAAGG:C	donor_loss	1.0000
17:45162857:AAGGT:A	donor_loss	1.0000
17:45162858:AGG:A	donor_loss	1.0000
17:45162860:G:GG	donor_gain	1.0000
17:45162861:T:A	donor_loss	1.0000
17:45162858:AG:A	donor_gain	0.9900
17:45162859:GG:G	donor_gain	0.9900
17:45169009:CTTTA:C	acceptor_loss	0.9900
17:45169010:TTTA:T	acceptor_loss	0.9900
17:45169011:TTAGA:T	acceptor_loss	0.9900
17:45169012:TA:T	acceptor_loss	0.9900
17:45169013:A:AC	acceptor_loss	0.9900
17:45169013:A:AG	acceptor_gain	0.9900
17:45169014:G:GT	acceptor_gain	0.9900
17:45169014:GA:G	acceptor_gain	0.9900
17:45169014:GAC:G	acceptor_gain	0.9900
17:45169014:GACC:G	acceptor_gain	0.9900
17:45169014:GACCT:G	acceptor_gain	0.9900
17:45161088:G:GT	donor_gain	0.9700
17:45161937:GAG:G	donor_gain	0.9700
17:45162747:CAGG:C	acceptor_loss	0.9700
17:45162748:A:G	acceptor_loss	0.9700
17:45162634:GG:G	donor_gain	0.9600
17:45162635:GG:G	donor_gain	0.9600
17:45162749:GGT:G	acceptor_gain	0.9600
17:45160827:TTTCC:T	donor_gain	0.9500
17:45161676:C:G	donor_gain	0.9500
17:45161732:G:GT	donor_gain	0.9500
17:45161935:AAGAG:A	donor_loss	0.9500
17:45161936:AGAG:A	donor_loss	0.9500

AlphaMissense

883 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:45169287:A:C	K113N	0.985
17:45169287:A:T	K113N	0.985
17:45169278:G:C	W110C	0.962
17:45169278:G:T	W110C	0.962
17:45169271:T:C	L108P	0.957
17:45169286:A:T	K113I	0.957
17:45169286:A:C	K113T	0.953
17:45169330:C:A	R128S	0.953
17:45169261:T:G	Y105D	0.950
17:45169273:A:C	S109R	0.943
17:45169275:C:A	S109R	0.943
17:45169275:C:G	S109R	0.943
17:45169342:T:C	F132L	0.943
17:45169344:C:A	F132L	0.943
17:45169344:C:G	F132L	0.943
17:45169285:A:G	K113E	0.942
17:45169261:T:C	Y105H	0.941
17:45169351:G:C	G135R	0.937
17:45169276:T:A	W110R	0.935
17:45169276:T:C	W110R	0.935
17:45169331:G:C	R128P	0.935
17:45169261:T:A	Y105N	0.933
17:45169295:G:C	R116P	0.928
17:45169222:C:A	R92S	0.913
17:45169340:T:C	M131T	0.913
17:45169297:G:C	D117H	0.912
17:45169351:G:T	G135C	0.912
17:45169341:G:A	M131I	0.908
17:45169341:G:C	M131I	0.908
17:45169341:G:T	M131I	0.908

dbSNP variants (sampled 300 via entrez): RS1000098491 (17:45166562 G>A), RS1000746769 (17:45160748 G>A), RS1000918152 (17:45161505 G>A), RS1000975087 (17:45161599 C>T), RS1001397804 (17:45166369 C>T), RS1001554649 (17:45167876 G>A,C), RS1001571153 (17:45164272 A>C,G), RS1001954280 (17:45160459 A>G), RS1002263651 (17:45167301 G>T), RS1002804327 (17:45159397 G>C), RS1003164379 (17:45159052 T>A), RS1003632121 (17:45159065 G>A), RS1003684551 (17:45158846 C>T), RS1003960965 (17:45160044 G>A,C), RS1004023592 (17:45165863 C>A,T)

Disease associations

OMIM: gene MIM:615695 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000395_1	Systolic blood pressure	1.000000e-08
GCST004412_12	Craniofacial microsomia	9.000000e-06
GCST006661_255	Male-pattern baldness	2.000000e-22
GCST008916_39	Asthma	8.000000e-12
GCST009798_36	Asthma	2.000000e-10
GCST010703_91	Brain morphology (MOSTest)	2.000000e-65

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Quercetin	decreases phosphorylation, decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	affects expression, decreases reaction, decreases expression, increases abundance	2
FR900359	increases phosphorylation	1
bisphenol A	decreases methylation	1
beta-lapachone	decreases expression	1
benzo(e)pyrene	decreases methylation	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects expression, decreases reaction	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Vehicle Emissions	affects expression, decreases reaction	1
Benzo(a)pyrene	decreases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Estradiol	decreases expression	1
Formaldehyde	increases expression	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	increases expression	1
Tunicamycin	increases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1

Clinical trials (associated diseases)

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