HIRA

Summary

HIRA (histone cell cycle regulator, HGNC:4916) is a protein-coding gene on chromosome 22q11.21, encoding Protein HIRA (P54198). Cooperates with ASF1A to promote replication-independent chromatin assembly. It is a selective cancer dependency (DepMap: 79.2% of cell lines).

This gene encodes a histone chaperone that preferentially places the variant histone H3.3 in nucleosomes. Orthologs of this gene in yeast, flies, and plants are necessary for the formation of transcriptionally silent heterochomatin. This gene plays an important role in the formation of the senescence-associated heterochromatin foci. These foci likely mediate the irreversible cell cycle changes that occur in senescent cells. It is considered the primary candidate gene in some haploinsufficiency syndromes such as DiGeorge syndrome, and insufficient production of the gene may disrupt normal embryonic development.

Source: NCBI Gene 7290 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 205 total
• Phenotypes (HPO): 131
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 79.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003325

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4916
Approved symbol	HIRA
Name	histone cell cycle regulator
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	DGCR1, TUP1
Ensembl gene	ENSG00000100084
Ensembl biotype	protein_coding
OMIM	600237
Entrez	7290

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263208, ENST00000340170, ENST00000452818, ENST00000464189, ENST00000935861, ENST00000935862, ENST00000935863, ENST00000935864, ENST00000935865, ENST00000935866, ENST00000935867, ENST00000935868, ENST00000935869, ENST00000935870

RefSeq mRNA: 1 — MANE Select: NM_003325 NM_003325

CCDS: CCDS13759

Canonical transcript exons

ENST00000263208 — 25 exons

Exon	Start	End
ENSE00000650719	19351358	19351446
ENSE00000650725	19355760	19355865
ENSE00001229731	19330698	19331556
ENSE00001933986	19431440	19431733
ENSE00003467908	19388484	19388554
ENSE00003470497	19383620	19383705
ENSE00003475462	19361727	19361931
ENSE00003478207	19397992	19398087
ENSE00003484139	19387711	19387816
ENSE00003489456	19359336	19359484
ENSE00003518651	19396787	19396947
ENSE00003527896	19361237	19361341
ENSE00003535922	19377869	19378066
ENSE00003555550	19356890	19357051
ENSE00003567968	19375631	19375792
ENSE00003569982	19394342	19394509
ENSE00003575047	19408483	19408593
ENSE00003580182	19353356	19353519
ENSE00003580891	19410716	19410778
ENSE00003595190	19405786	19405880
ENSE00003650304	19392101	19392214
ENSE00003676847	19356230	19356288
ENSE00003683638	19385521	19385736
ENSE00003693401	19353996	19354118
ENSE00003694241	19407184	19407274

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 94.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.9424 / max 163.6229, expressed in 1821 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193151	30.9424	1821
193147	13.3584	1801
193150	1.7830	509
193149	1.4881	523
193148	0.8854	553

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left lobe of thyroid gland	UBERON:0001120	94.58	gold quality
thyroid gland	UBERON:0002046	94.54	gold quality
right lobe of thyroid gland	UBERON:0001119	94.51	gold quality
cortical plate	UBERON:0005343	90.76	gold quality
granulocyte	CL:0000094	89.13	gold quality
ventricular zone	UBERON:0003053	88.51	gold quality
ganglionic eminence	UBERON:0004023	88.29	gold quality
stromal cell of endometrium	CL:0002255	87.58	gold quality
gastrocnemius	UBERON:0001388	87.40	gold quality
right frontal lobe	UBERON:0002810	87.32	gold quality
prefrontal cortex	UBERON:0000451	87.09	gold quality
thymus	UBERON:0002370	87.04	silver quality
blood vessel layer	UBERON:0004797	86.88	gold quality
embryo	UBERON:0000922	86.86	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.57	gold quality
amygdala	UBERON:0001876	86.50	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.38	gold quality
penis	UBERON:0000989	86.34	silver quality
muscle of leg	UBERON:0001383	86.33	gold quality
cerebellar hemisphere	UBERON:0002245	86.27	gold quality
skin of hip	UBERON:0001554	86.23	gold quality
cerebellar cortex	UBERON:0002129	86.23	gold quality
cerebellum	UBERON:0002037	86.17	gold quality
mucosa of transverse colon	UBERON:0004991	86.17	gold quality
cingulate cortex	UBERON:0003027	86.14	gold quality
bone marrow	UBERON:0002371	86.10	gold quality
anterior cingulate cortex	UBERON:0009835	86.09	gold quality
neocortex	UBERON:0001950	85.96	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.85	silver quality
frontal cortex	UBERON:0001870	85.82	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	43.01
E-ANND-3	no	2.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
PLB1	Repression

Upstream regulators (CollecTRI, top): APEX1

miRNA regulators (miRDB)

60 targeting HIRA, 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-7110-3P	100.00	73.18	2486
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
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-335-3P	99.93	73.36	4958
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4729	99.69	72.18	4233

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 79.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 34)

• the N-terminal half of HIRA should contribute positively to the growth rate via up-regulation of a set of cell cycle-related genes, whereas the C-terminal half down-regulated another set of them without exhibiting any effect on the cell growth (PMID:16024922)
• The N- and C-terminal regions of ASF1a and ASF1b determine the different affinities of these two proteins for HIRA, by contacting regions outside the HIRA B domain. CAF-1 also uses B domain-like motifs for binding to ASF1a, thereby competing with HIRA. (PMID:16980972)
• Hpc2-related domain of UBN1, UBN2, and Hpc2p is an evolutionarily conserved HIRA/Hir-binding domain, which directly interacts with the N-terminal WD repeats of HIRA/Hir. (PMID:19029251)
• FISH analysis of metaphases revealed a duplication of TUPLE1 probe on one chromosome 22q (Fig. 1). (PMID:19046189)
• HIRA plays a unique, ASF1a-independent role, which is required for the localization of HP1 (PMID:21347226)
• phosphorylation of histone H4 Ser 47 catalyzed by the PAK2 kinase, promotes nucleosome assembly of H3.3-H4 and inhibits nucleosome assembly of H3.1-H4 by increasing the binding affinity of HIRA to H3.3-H4 and reducing association of CAF-1 with H3.1-H4 (PMID:21724829)
• Data show that, like HIRA, UBN1, and ASF1a, CABIN1 is involved in heterochromatinization of the genome of senescent human cells. (PMID:21807893)
• NHRD domain of UBN1 as being an essential region for HIRA interaction and chromatin organization by the HUCA complex (PMID:22401310)
• HIRA is required for deposition of histone H3.3 at its binding sites. (PMID:23602572)
• Mechanistic studies reveal that HIRA accumulates at sites of UVC irradiation upon detection of DNA damage prior to repair and deposits newly synthesized H3.3 histones. This local action of HIRA depends on ubiquitylation events associated with damage recognition. (PMID:24074863)
• HIRA controls a specialized, dynamic H4K16ac-decorated chromatin landscape in senescent cells and enforces tumor suppression. (PMID:25512559)
• These results support a model in which OGT modifies HIRA to regulate HIRA-H3.3 complex formation and H3.3 nucleosome assembly and reveal the mechanism by which OGT functions in cellular senescence. (PMID:27217568)
• Chromatin reassembly during double-strand break repair was dependent on the HIRA histone chaperone that is specific to the replication-independent histone variant H3.3 and on CAF-1 that is specific to the replication-dependent canonical histones H3.1/H3.2. (PMID:27269284)
• These data show that HIRA phosphorylation limits the expression of myogenic genes, while the dephosphorylation of HIRA is required for proficient H3.3 deposition and gene activation, demonstrating that the phosphorylation switch is exploited to modulate HIRA/H3.3-mediated muscle gene regulation during myogenesis. (PMID:27515126)
• The abnormal lower expression of the HIRA gene in the myocardium may participate in the pathogenesis of Tetralogy of Fallot. (PMID:27748330)
• PHB has an unexpected nuclear role in human embryonic stem cells that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit. (PMID:27939217)
• RPA, best known for its role in DNA replication and repair, recruits HIRA to promoters and enhancers and regulates deposition of newly synthesized H3.3 to these regulatory elements for gene regulation. (PMID:28107649)
• H3.Y discriminates between HIRA and DAXX chaperone complexes and reveals unexpected insights into human DAXX-H3.3-H4 binding and deposition requirements. (PMID:28334823)
• Data show that histone chaperone HIRA co-localizes with viral genomes, binds to incoming viral and deposits histone H3.3 onto these. (PMID:28981850)
• analysis of the trimeric HIRA, UBN1 and CABIN1 H3.3 histone chaperone complex (PMID:30082790)
• H3.3 chaperones HIRA and DAXX promote ectopic CENP-A deposition. (PMID:30365520)
• Two HIRA-dependent pathways mediate H3.3 de novo deposition and recycling during transcription. (PMID:32895554)
• Histone Loaders CAF1 and HIRA Restrict Epstein-Barr Virus B-Cell Lytic Reactivation. (PMID:33109754)
• Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth. (PMID:33417013)
• HIRA contributes to zygote formation in mice and is implicated in human 1PN zygote phenotype. (PMID:33835048)
• Haploinsufficiency of the HIRA gene may not always produce severe neurodevelopmental consequences. (PMID:34074949)
• Dissecting regulatory pathways for transcription recovery following DNA damage reveals a non-canonical function of the histone chaperone HIRA. (PMID:34158510)
• DNA methylation mediated downregulation of histone H3 variant H3.3 affects cell proliferation contributing to the development of HCC. (PMID:34626773)
• HIRA Supports Hepatitis B Virus Minichromosome Establishment and Transcriptional Activity in Infected Hepatocytes. (PMID:35643233)
• Interplay between PML NBs and HIRA for H3.3 dynamics following type I interferon stimulus. (PMID:37227756)
• HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers. (PMID:37638746)
• Disparity of gene expression in coronary artery disease: insights from MEIS1, HIRA, and Myocardin. (PMID:38824221)
• Histone H3.3 chaperone HIRA renders stress-responsive genes poised for prospective lethal stresses in acquired tolerance. (PMID:38977420)
• Histone chaperone HIRA, promyelocytic leukemia protein, and p62/SQSTM1 coordinate to regulate inflammation during cell senescence. (PMID:39178863)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hira	ENSDARG00000013434
mus_musculus	Hira	ENSMUSG00000022702
rattus_norvegicus	Hira	ENSRNOG00000045770
drosophila_melanogaster	Hira	FBGN0022786
caenorhabditis_elegans		WBGENE00019627

Protein

Protein identifiers

Protein HIRA — P54198 (reviewed: P54198)

Alternative names: TUP1-like enhancer of split protein 1

All UniProt accessions (2): P54198, H7C2A7

UniProt curated annotations — full annotation on UniProt →

Function. Cooperates with ASF1A to promote replication-independent chromatin assembly. Required for the periodic repression of histone gene transcription during the cell cycle. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit.

Subunit / interactions. Interacts with histone H3-3B, PAX3 and PAX7. Interacts with histone H3.Y. Interacts with CCNA1, HIRIP3, NFU1/HIRIP5 and histone H2B. Part of a complex which includes ASF1A, CABIN1, histone H3.3, histone H4 and UBN1.

Subcellular location. Nucleus. PML body.

Tissue specificity. Expressed at high levels in kidney, pancreas and skeletal muscle and at lower levels in brain, heart, liver, lung, and placenta.

Post-translational modifications. Sumoylated. Phosphorylated by CDK2/CCNA1 and CDK2/CCNE1 on Thr-555 in vitro. Also phosphorylated on Thr-555 and Ser-687 in vivo.

Similarity. Belongs to the WD repeat HIR1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P54198-1	Long	yes
P54198-2	Short

RefSeq proteins (1): NP_003316* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR011494	HIRA-like_C	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR031120	HIR1-like	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR055410	Beta-prop_CAF1B_HIR1	Domain

Pfam: PF07569, PF24105

UniProt features (87 total): strand 20, mutagenesis site 15, modified residue 14, region of interest 10, helix 9, repeat 7, turn 4, compositionally biased region 3, sequence conflict 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5YJE	X-RAY DIFFRACTION	2.45
2I32	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54198-F1	75.20	0.53

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 (14): 111, 549, 555, 557, 576, 584, 586, 610, 611, 612, 614, 661, 675, 687

Mutagenesis-validated functional residues (15):

Position	Phenotype
449–458	impairs binding to asf1a.
458–460	abrogates binding to asf1a.
458–460	impairs binding to asf1a.
458–459	impairs binding to asf1a.
458	impairs binding to asf1a.
458	impairs binding to asf1a; when associated with k-460.
459–468	abrogates binding to asf1a.
459	abrogates binding to asf1a.
460	abrogates binding to asf1a.
460	impairs binding to asf1a; when associated with k-458.
461	abrogates binding to asf1a.
464	impairs binding to asf1a.
466	impairs binding to asf1a.
555	impairs phosphorylation by cdk2.
628–631	impairs binding to ccna1 and phosphorylation by cdk2.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2559584	Formation of Senescence-Associated Heterochromatin Foci (SAHF)
R-HSA-9821993	Replacement of protamines by nucleosomes in the male pronucleus

MSigDB gene sets: 505 (showing top): RNGTGGGC_UNKNOWN, E2F_Q4, E2F4DP1_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, LFA1_Q6, GCANCTGNY_MYOD_Q6, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_OSTEOBLAST_DIFFERENTIATION, AP2_Q3, PUJANA_CHEK2_PCC_NETWORK, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, MODULE_331, E2F1DP1_01, E2F1DP2_01

GO Biological Process (11): osteoblast differentiation (GO:0001649), nucleosome assembly (GO:0006334), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), gastrulation (GO:0007369), anatomical structure morphogenesis (GO:0009653), muscle cell differentiation (GO:0042692), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (5): transcription corepressor activity (GO:0003714), histone binding (GO:0042393), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515), nucleosome binding (GO:0031491)

GO Cellular Component (7): HIR complex (GO:0000417), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), PML body (GO:0016605), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
DNA Damage/Telomere Stress Induced Senescence	1
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
chromatin organization	2
regulation of DNA-templated transcription	2
DNA-templated transcription	2
cellular anatomical structure	2
ossification	1
nucleosome organization	1
protein-DNA complex assembly	1
gene expression	1
RNA biosynthetic process	1
transcription by RNA polymerase II	1
ectoderm formation	1
endoderm formation	1
mesoderm formation	1
embryonic morphogenesis	1
developmental process	1
anatomical structure development	1
muscle structure development	1
cellular component organization	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
negative regulation of RNA biosynthetic process	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
protein binding	1
DNA-binding transcription factor binding	1
binding	1
chromatin binding	1
protein-containing complex binding	1
protein-containing complex	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear body	1
cellular_component	1
extracellular vesicle	1

Protein interactions and networks

STRING

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIRA	CABIN1	Q9Y6J0	993
HIRA	UBN1	Q9NPG3	983
HIRA	ASF1A	Q9Y294	880
HIRA	DGCR2	P98153	857
HIRA	HIRIP3	Q9BW71	816
HIRA	ZNF74	Q16587	775
HIRA	SMTN	P53814	763
HIRA	DGCR6	Q14129	762
HIRA	DGCR6L	Q9BY27	756
HIRA	ESS2	Q96DF8	726
HIRA	ATRX	P46100	681
HIRA	TBX1	O43435	663
HIRA	DAXX	Q9UER7	662
HIRA	COMT	P21964	655
HIRA	SLC25A1	P53007	639

IntAct

123 interactions, top by confidence:

A	B	Type	Score
HIRA	ASF1A	psi-mi:“MI:0915”(physical association)	0.900
ASF1A	HIRA	psi-mi:“MI:0914”(association)	0.900
HIRA	ASF1A	psi-mi:“MI:0407”(direct interaction)	0.900
HIRA	ASF1B	psi-mi:“MI:0407”(direct interaction)	0.830
UBN1	HIRA	psi-mi:“MI:0914”(association)	0.710
HIRA	UBN1	psi-mi:“MI:0914”(association)	0.710
HIRA	UBN1	psi-mi:“MI:0915”(physical association)	0.710
HIRA	UBN1	psi-mi:“MI:0407”(direct interaction)	0.710
H3-3A	HIRA	psi-mi:“MI:0914”(association)	0.640
ASF1A	HAT1	psi-mi:“MI:0914”(association)	0.640
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640

BioGRID (253): HIRA (Affinity Capture-RNA), HIRA (Affinity Capture-RNA), HIRA (Biochemical Activity), HIRA (Proximity Label-MS), HIRA (Affinity Capture-MS), HIRA (Affinity Capture-MS), HIRA (Affinity Capture-MS), HIRA (Affinity Capture-MS), HIRA (Affinity Capture-MS), HIRA (Affinity Capture-MS), HIRA (Two-hybrid), HIRA (Two-hybrid), HIRA (Affinity Capture-MS), HIRA (Affinity Capture-MS), HIRA (Affinity Capture-MS)

ESM2 similar proteins: A0A8J1LLF7, A0A974H8H3, A0MQH0, A4FUD6, A5HK05, B3DLA6, P11029, P11497, P42694, P54198, Q13085, Q25BN1, Q28559, Q4R4U1, Q504Q3, Q5R5F8, Q5R660, Q5R8I6, Q5RCC1, Q5SWU9, Q5ZIT8, Q6DFV5, Q6IE70, Q6NYU2, Q6P1X5, Q6TUI4, Q6TV19, Q80YV4, Q8BGF7, Q8BHL5, Q8BPU7, Q8C176, Q8CIQ7, Q8IZD9, Q8K0F1, Q8R418, Q8R5L3, Q8VHE0, Q923S8, Q92556

Diamond homologs: A1CQL6, A1D3I2, A2QPW4, A3LVM1, A5DHD2, A5DXE2, A5E2R6, A6RT32, A6ZYM0, A7RWD2, A7TLU2, A8PWQ8, B0XAF3, B0XQ15, B3RNR8, B6H7A3, B6K1G6, B7QKS1, B8MWR8, B9WHJ2, C1BK83, D4AZ50, D4DG66, F1LTR1, O17468, O42611, O80990, P0CS30, P0CS31, P54198, P79987, Q05583, Q0CCS0, Q0USG2, Q17GR9, Q1DR81, Q2UG43, Q2UPI0, Q4ICM0, Q4P5F5

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CDK2	“up-regulates activity”	HIRA	phosphorylation
CyclinE/CDK2	up-regulates	HIRA	phosphorylation
HIRA	“form complex”	“HIRA complex 1”	binding
HIRA	“form complex”	“HIRA complex 2”	binding
AKT1	“up-regulates activity”	HIRA	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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
Transcriptional regulation by RUNX3	5	16.2×	1e-03
mRNA 3’-end processing	5	11.7×	4e-03
mRNA Splicing	7	9.2×	1e-03
Regulation of PD-L1(CD274) transcription	7	9.1×	1e-03
Processing of Capped Intron-Containing Pre-mRNA	8	7.8×	1e-03
mRNA Splicing - Major Pathway	12	7.8×	9e-06
mRNA Polyadenylation	7	7.3×	3e-03
Dengue Virus-Host Interactions	13	7.1×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	10	12.3×	2e-06
mRNA splicing, via spliceosome	10	8.0×	9e-05
mRNA processing	8	5.5×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	109
Likely benign	36
Benign	30

Top pathogenic / likely-pathogenic (0)

SpliceAI

5566 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19331555:CC:C	acceptor_gain	1.0000
22:19331556:CC:C	acceptor_gain	1.0000
22:19331556:CCT:C	acceptor_loss	1.0000
22:19331557:C:A	acceptor_loss	1.0000
22:19331557:C:CC	acceptor_gain	1.0000
22:19331558:T:G	acceptor_loss	1.0000
22:19351445:CC:C	acceptor_gain	1.0000
22:19351446:CC:C	acceptor_gain	1.0000
22:19351447:C:T	acceptor_gain	1.0000
22:19353352:TCAC:T	donor_loss	1.0000
22:19353353:CACCT:C	donor_loss	1.0000
22:19353354:A:C	donor_loss	1.0000
22:19353355:C:T	donor_loss	1.0000
22:19353355:CCTT:C	donor_gain	1.0000
22:19353515:CCGAG:C	acceptor_gain	1.0000
22:19353516:CGAG:C	acceptor_gain	1.0000
22:19353516:CGAGC:C	acceptor_gain	1.0000
22:19353517:GAG:G	acceptor_gain	1.0000
22:19353520:C:CC	acceptor_gain	1.0000
22:19353530:C:CT	acceptor_gain	1.0000
22:19355862:CTTC:C	acceptor_gain	1.0000
22:19359331:CTTA:C	donor_loss	1.0000
22:19359332:TTAC:T	donor_loss	1.0000
22:19359334:A:C	donor_loss	1.0000
22:19359335:CCAG:C	donor_gain	1.0000
22:19359389:C:A	donor_gain	1.0000
22:19361342:C:CC	acceptor_gain	1.0000
22:19361932:C:CA	acceptor_loss	1.0000
22:19375626:CCTA:C	donor_loss	1.0000
22:19375628:TA:T	donor_loss	1.0000

AlphaMissense

6628 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19383638:A:T	I466K	1.000
22:19383647:G:C	P463R	1.000
22:19383647:G:T	P463H	1.000
22:19383648:G:A	P463S	1.000
22:19383648:G:T	P463T	1.000
22:19383653:A:C	I461S	1.000
22:19383653:A:G	I461T	1.000
22:19383653:A:T	I461N	1.000
22:19383655:T:A	R460S	1.000
22:19383655:T:G	R460S	1.000
22:19383656:C:A	R460I	1.000
22:19383656:C:G	R460T	1.000
22:19383657:T:C	R460G	1.000
22:19383658:T:A	R459S	1.000
22:19383658:T:G	R459S	1.000
22:19383659:C:A	R459I	1.000
22:19383659:C:G	R459T	1.000
22:19383660:T:C	R459G	1.000
22:19383662:C:G	R458P	1.000
22:19383665:C:A	G457V	1.000
22:19383665:C:T	G457D	1.000
22:19383666:C:A	G457C	1.000
22:19383666:C:G	G457R	1.000
22:19383682:C:A	E451D	1.000
22:19383682:C:G	E451D	1.000
22:19383684:C:T	E451K	1.000
22:19383688:T:A	Q449H	1.000
22:19383688:T:G	Q449H	1.000
22:19387737:C:G	G363R	1.000
22:19387739:A:G	L362P	1.000

dbSNP variants (sampled 300 via entrez): RS1000008427 (22:19384281 G>A), RS1000109352 (22:19331118 T>A,C), RS1000115528 (22:19334225 T>C), RS1000124048 (22:19373468 T>C), RS1000136261 (22:19426512 C>T), RS1000249912 (22:19432446 A>T), RS1000252918 (22:19404029 AT>A,ATT), RS1000262032 (22:19363045 C>A), RS1000282715 (22:19391513 G>A), RS1000316144 (22:19363243 A>C), RS1000340621 (22:19375216 T>C), RS1000390613 (22:19348036 T>C), RS1000429463 (22:19407956 A>G), RS1000528305 (22:19384518 A>G), RS1000564940 (22:19378791 A>G)

Disease associations

OMIM: gene MIM:600237 | disease phenotypes: MIM:606232, MIM:616435

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (4): prostate cancer (MONDO:0008315), Phelan-McDermid syndrome (MONDO:0011652), Fanconi anemia complementation group T (MONDO:0014638), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Familial prostate cancer (Orphanet:1331), Phelan-McDermid syndrome (Orphanet:48652), Fanconi anemia (Orphanet:84)

HPO phenotypes

131 total (30 of 131 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000089	Renal hypoplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000130	Abnormality of the uterus
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000389	Chronic otitis media
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003075_3	Cognitive decline rate in late mild cognitive impairment	4.000000e-06
GCST003075_67	Cognitive decline rate in late mild cognitive impairment	9.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C536801	Telomeric 22q13 Monosomy Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724675 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.76	IC50	1750	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178674: Inhibition of HIRA (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.7500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Estradiol	increases expression	3
bisphenol A	increases methylation, decreases expression, affects cotreatment	2
trichostatin A	increases expression, affects cotreatment	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	decreases expression	1
potassium perchlorate	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Amiodarone	increases expression	1
Benzo(a)pyrene	decreases expression	1
Biotin	decreases expression	1
Cadmium	decreases expression	1
Caffeine	affects phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tretinoin	decreases expression	1
Triiodothyronine	increases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases 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
CHEMBL5697404	Binding	Inhibition of HIRA (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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery