NFYA

Summary

NFYA (nuclear transcription factor Y subunit alpha, HGNC:7804) is a protein-coding gene on chromosome 6p21.1, encoding Nuclear transcription factor Y subunit alpha (P23511). Component of the sequence-specific heterotrimeric transcription factor (NF-Y) which specifically recognizes a 5’-CCAAT-3’ box motif found in the promoters of its target genes. It is a selective cancer dependency (DepMap: 12.3% of cell lines).

The protein encoded by this gene is one subunit of a trimeric complex, forming a highly conserved transcription factor that binds to CCAAT motifs in the promoter regions in a variety of genes. Subunit A associates with a tight dimer composed of the B and C subunits, resulting in a trimer that binds to DNA with high specificity and affinity. The sequence specific interactions of the complex are made by the A subunit, suggesting a role as the regulatory subunit. In addition, there is evidence of post-transcriptional regulation in this gene product, either by protein degradation or control of translation. Further regulation is represented by alternative splicing in the glutamine-rich activation domain, with clear tissue-specific preferences for the two isoforms.

Source: NCBI Gene 4800 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 29 total
• GTEx eGene: eQTL in 37 tissues, sQTL in 5 (q < 0.05)
• Cancer dependency (DepMap): dependent in 12.3% of screened cell lines
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 0.68 (unconstrained)
• Transcription factor: yes — 98 downstream targets (CollecTRI)
• MANE Select transcript: NM_002505

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7804
Approved symbol	NFYA
Name	nuclear transcription factor Y subunit alpha
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	HAP2, CBF-B, NF-YA
Ensembl gene	ENSG00000001167
Ensembl biotype	protein_coding
OMIM	189903
Entrez	4800

Gene structure

Transcript identifiers

Ensembl transcripts: 57 — 56 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000341376

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 5: 1

ENST00000341376, ENST00000353205, ENST00000902856, ENST00000902857, ENST00000902858, ENST00000902859, ENST00000902860, ENST00000902861, ENST00000902862, ENST00000902863, ENST00000902864, ENST00000902865, ENST00000902866, ENST00000902867, ENST00000902868, ENST00000902869, ENST00000902870, ENST00000902871, ENST00000902872, ENST00000902873, ENST00000902874, ENST00000902875, ENST00000902876, ENST00000902877, ENST00000914455, ENST00000914456, ENST00000914457, ENST00000914458, ENST00000914459, ENST00000914460, ENST00000914461, ENST00000914462, ENST00000914463, ENST00000914464, ENST00000914465, ENST00000914466, ENST00000914467, ENST00000955092, ENST00000955093, ENST00000955094, ENST00000955095, ENST00000955096, ENST00000955097, ENST00000955098, ENST00000955099, ENST00000955100, ENST00000955101, ENST00000955102, ENST00000955103, ENST00000955104, ENST00000955105, ENST00000955106, ENST00000974835, ENST00000974836, ENST00001085372, ENST00001085373, ENST00001135335

RefSeq mRNA: 2 — MANE Select: NM_002505 NM_002505, NM_021705

CCDS: CCDS4849, CCDS4850

Canonical transcript exons

ENST00000341376 — 10 exons

Exon	Start	End
ENSE00000750570	41094396	41094497
ENSE00000750577	41091528	41091694
ENSE00000750637	41084046	41084192
ENSE00000849858	41079029	41079164
ENSE00000849861	41089579	41089710
ENSE00000849862	41090204	41090309
ENSE00000849864	41092912	41093085
ENSE00001299015	41097357	41102403
ENSE00001382968	41080811	41080897
ENSE00001924448	41072974	41073084

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 94.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.1390 / max 305.7493, expressed in 1817 samples.

Highest expression (Bgee): cortical plate, buccal mucosa cell, ganglionic eminence, testis, sperm.

Genetic regulation across tissues (GTEx eQTL / sQTL)

NFYA is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 37 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 42 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	9.0e-70	+0.90	6:41130771:AG:A
Nerve Tibial	eqtl	3.8e-40	+0.63	6:41130771:AG:A
Testis	eqtl	2.0e-32	+0.36	6:41052771:G:T
Pancreas	eqtl	2.9e-21	+0.63	6:41146182:T:C
Breast Mammary Tissue	eqtl	6.9e-20	+0.52	6:41133122:C:G
Adipose Subcutaneous	eqtl	1.9e-15	+0.35	6:41153359:G:A
Skin Not Sun Exposed Suprapubic	eqtl	2.8e-15	+0.30	6:41137738:T:TGAA
Adipose Visceral Omentum	eqtl	6.4e-13	+0.42	6:41130771:AG:A
Esophagus Gastroesophageal Junction	eqtl	1.3e-12	+0.48	6:41145639:G:A
Skin Sun Exposed Lower leg	eqtl	1.5e-11	+0.34	6:41145790:T:G
Colon Transverse	eqtl	1.9e-11	+0.33	6:41138475:A:C
Artery Tibial	eqtl	2.8e-11	+0.37	6:41130771:AG:A
Testis	sqtl	2.3e-09	+0.53	6:41077540:ATGTAT:A
Muscle Skeletal	eqtl	7.5e-09	+0.31	6:41138475:A:C
Brain Cerebellar Hemisphere	eqtl	1.1e-08	+0.45	6:41145639:G:A
Esophagus Muscularis	eqtl	1.7e-08	+0.39	6:41146182:T:C
Artery Aorta	eqtl	2.1e-08	+0.42	6:41101050:C:A
Lung	eqtl	2.4e-08	+0.24	6:41100861:A:G
Spleen	eqtl	1.3e-07	+0.58	6:41100841:G:C
Colon Sigmoid	eqtl	1.9e-07	+0.39	6:41133122:C:G

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
67732	22.9147	1813
67735	3.4430	1239
67733	0.4093	212
67734	0.3081	164
203988	0.0638	23

Top tissues by expression

showing 100 of 283 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	94.13	gold quality
buccal mucosa cell	CL:0002336	90.86	gold quality
ganglionic eminence	UBERON:0004023	90.56	gold quality
right testis	UBERON:0004534	90.41	gold quality
left testis	UBERON:0004533	90.32	gold quality
sperm	CL:0000019	90.09	gold quality
testis	UBERON:0000473	89.67	gold quality
embryo	UBERON:0000922	89.52	gold quality
male germ cell	CL:0000015	89.29	gold quality
secondary oocyte	CL:0000655	87.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.49	gold quality
bone marrow cell	CL:0002092	87.31	gold quality
islet of Langerhans	UBERON:0000006	87.09	gold quality
monocyte	CL:0000576	87.01	gold quality
leukocyte	CL:0000738	86.81	gold quality
stromal cell of endometrium	CL:0002255	86.79	gold quality
mononuclear cell	CL:0000842	86.77	gold quality
ventricular zone	UBERON:0003053	86.32	gold quality
bone marrow	UBERON:0002371	86.10	gold quality
middle temporal gyrus	UBERON:0002771	85.89	gold quality
rectum	UBERON:0001052	84.94	gold quality
blood	UBERON:0000178	84.60	gold quality
right lobe of thyroid gland	UBERON:0001119	84.41	gold quality
lymph node	UBERON:0000029	84.32	gold quality
tendon of biceps brachii	UBERON:0008188	84.12	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.06	gold quality
granulocyte	CL:0000094	83.99	gold quality
medial globus pallidus	UBERON:0002477	83.87	gold quality
Brodmann (1909) area 23	UBERON:0013554	83.81	silver quality
left ovary	UBERON:0002119	83.75	gold quality
gall bladder	UBERON:0002110	83.73	gold quality
ovary	UBERON:0000992	83.65	gold quality
calcaneal tendon	UBERON:0003701	83.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.49	gold quality
oocyte	CL:0000023	83.48	gold quality
left lobe of thyroid gland	UBERON:0001120	83.39	gold quality
thyroid gland	UBERON:0002046	83.39	gold quality
corpus callosum	UBERON:0002336	83.36	gold quality
endometrium	UBERON:0001295	83.23	gold quality
tendon	UBERON:0000043	82.94	gold quality
pancreas	UBERON:0001264	82.85	gold quality
spinal cord	UBERON:0002240	82.78	gold quality
right ovary	UBERON:0002118	82.69	gold quality
smooth muscle tissue	UBERON:0001135	82.06	gold quality
vermiform appendix	UBERON:0001154	81.74	gold quality
choroid plexus epithelium	UBERON:0003911	81.74	gold quality
primary visual cortex	UBERON:0002436	81.73	gold quality
globus pallidus	UBERON:0001875	81.72	gold quality
body of pancreas	UBERON:0001150	81.66	gold quality
adrenal tissue	UBERON:0018303	81.38	gold quality
omental fat pad	UBERON:0010414	81.32	gold quality
peritoneum	UBERON:0002358	81.31	gold quality
amygdala	UBERON:0001876	81.26	gold quality
esophagus mucosa	UBERON:0002469	80.90	gold quality
caecum	UBERON:0001153	80.83	gold quality
endocervix	UBERON:0000458	80.82	gold quality
ectocervix	UBERON:0012249	80.82	gold quality
gastrocnemius	UBERON:0001388	80.77	gold quality
right adrenal gland cortex	UBERON:0035827	80.74	gold quality
left uterine tube	UBERON:0001303	80.73	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.72	gold quality
right lung	UBERON:0002167	80.59	gold quality
lower esophagus mucosa	UBERON:0035834	80.58	gold quality
right adrenal gland	UBERON:0001233	80.57	gold quality
upper lobe of left lung	UBERON:0008952	80.55	gold quality
muscle of leg	UBERON:0001383	80.54	gold quality
female reproductive system	UBERON:0000474	80.52	gold quality
left adrenal gland	UBERON:0001234	80.51	gold quality
body of stomach	UBERON:0001161	80.44	gold quality
right lobe of liver	UBERON:0001114	80.42	gold quality
uterus	UBERON:0000995	80.33	gold quality
body of uterus	UBERON:0009853	80.19	gold quality
putamen	UBERON:0001874	80.16	gold quality
left adrenal gland cortex	UBERON:0035825	80.09	gold quality
adrenal gland	UBERON:0002369	80.07	gold quality
apex of heart	UBERON:0002098	80.00	gold quality
spleen	UBERON:0002106	79.95	gold quality
adrenal cortex	UBERON:0001235	79.93	gold quality
colonic epithelium	UBERON:0000397	79.90	gold quality
vagina	UBERON:0000996	79.90	gold quality
upper lobe of lung	UBERON:0008948	79.90	gold quality
thymus	UBERON:0002370	79.80	gold quality
stomach	UBERON:0000945	79.74	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.57	gold quality
tonsil	UBERON:0002372	79.56	gold quality
mucosa of transverse colon	UBERON:0004991	79.51	gold quality
minor salivary gland	UBERON:0001830	79.48	gold quality
transverse colon	UBERON:0001157	79.46	gold quality
anatomical system	UBERON:0000467	79.41	gold quality
prefrontal cortex	UBERON:0000451	79.39	gold quality
skin of abdomen	UBERON:0001416	79.33	gold quality
occipital lobe	UBERON:0002021	79.31	gold quality
material anatomical entity	UBERON:0000465	79.28	gold quality
multicellular organism	UBERON:0000468	79.27	gold quality
caudate nucleus	UBERON:0001873	79.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.23	gold quality
esophagus	UBERON:0001043	79.12	gold quality
right frontal lobe	UBERON:0002810	79.11	gold quality
substantia nigra	UBERON:0002038	79.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.56

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	36.2	medium
Thymus	tissue	35.7
Testis	tissue	33.6	high
Nucleus accumbens	tissue	26.3
Hippocampus	tissue	23.3	low
Locus coeruleus	tissue	21.9
Postcentral gyrus	tissue	21.2
Choroid plexus	tissue	20.9
Retina	tissue	18.4
Tonsil	tissue	17.3	medium
Lymph node	tissue	16.1
Thyroid gland	tissue	15.7	medium
Ovary	tissue	15.5	medium
Caudate putamen	tissue	14.9
Parathyroid gland	tissue	13.4	medium
Breast	tissue	13.1	medium
Frontal cortex	tissue	13.0
Endometrium 1	tissue	12.8	medium
Rectum	tissue	12.6	medium
Urinary bladder	tissue	12.5	medium
Epididymis	tissue	12.3	medium
Spleen	tissue	12.2	medium
Liver	tissue	12.2	medium
Appendix	tissue	12.1	medium
Placenta	tissue	11.8	medium
Corpus callosum	tissue	11.8
Prostate	tissue	11.4	medium
Hippocampal formation	tissue	11.2
Tongue	tissue	11.0
Stomach 1	tissue	10.9	medium
Hypothalamus	tissue	10.8
Gallbladder	tissue	10.8	medium
Spinal cord	tissue	10.7
Septum	tissue	10.5
Substantia nigra	tissue	10.4
Pons	tissue	10.2
Pancreas	tissue	10.2	medium
Midbrain	tissue	10.2
Colon	tissue	10.1	medium
Medulla oblongata	tissue	10.1
Lung	tissue	10.1	high
Periaqueductal gray	tissue	10.1
Fallopian tube	tissue	10.0	medium
Superior colliculi	tissue	9.8
Small intestine	tissue	9.8	medium
Amygdala	tissue	9.7
Smooth muscle	tissue	9.6	medium
Putamen	tissue	9.6
Cervix	tissue	9.5	medium
Ventral forebrain	tissue	9.5
Olfactory bulb	tissue	9.5
Adipose tissue	tissue	9.4	not detected
Thalamus	tissue	9.4
Cerebellum	tissue	9.2	medium
Cerebral cortex	tissue	9.1	medium
Motor cortex	tissue	9.1
Somatosensory cortex	tissue	9.1
Entorhinal cortex	tissue	9.0
Skin 1	tissue	8.9	medium
Temporal cortex	tissue	8.9

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Parieto-temporal junction (white matter) (48.8), Temporal white matter (47.2), Corpus callosum, genu (white matter) (40.8), Angular gyrus (white matter) (39.1), Corpus callosum, splenium (white matter) (39.1).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 98 targets:

Target	Regulation
ABCB1	Unknown
ACLY
ACSBG1
ACTB	Activation
ADAM2
ADIPOQ
AKR1C1
AMELX	Activation
ASF1A
ASF1B	Activation
AURKA	Activation
BMAL1
CASP1
CBS	Activation
CCNB2	Unknown
CCND2	Activation
CDC25A	Activation
CDC25C	Activation
CDK1	Repression
CDKN1B	Activation
CDKN2A
CGA	Unknown
CHEK2	Repression
CLDN11	Activation
COL1A2	Activation
CYC1	Unknown
CYP2A6	Activation
DDIT3	Unknown
DLST
E2F1	Activation

JASPAR motifs

Motif	Name	Family
MA0060.1	NFYA	Heteromeric CCAAT-binding
MA0060.2	NFYA	Heteromeric CCAAT-binding
MA0060.3	NFYA	Heteromeric CCAAT-binding
MA0060.4	NFYA	Heteromeric CCAAT-binding

JASPAR matrix evidence (PMIDs): PMID:9469818

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CREB1, DDIT3, E2F1, ESR1, ETV4, FOXA2, FOXC1, GATA4, HOXB4, IRF6, JUN, KAT7, MEIS1, MYBL2, NFKB, NFYA, NFYB, NFYC, NR1H3, POU2F1, SP1, SP3, SREBF1, TCF3, TP53, TP63, TP73, USF1, ZHX2, ZNF148, ZNF160

miRNA regulators (miRDB)

Targeting NFYA by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 177 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-545-3P	99.95	70.74	2783

Functional genomics

gnomAD constraint: pLI 0.00661, LOEUF 0.68, missense Z 3.8 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000341376 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
6:41,079,090–41,090,227	118 / 182.4	0.65	no
6:41,090,228–41,094,468	81 / 210.5	0.38	no
6:41,094,469–41,097,407	35 / 34.2	1.02	no
DepMap (CRISPR cell-line fitness): dependent in 12.3% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): LPS6 (-1.24), H3118 (-1.078), HEC-116 (-1.065), T3M-5 (-1.015), OVCA420 (-1.003), HUP-T3 (-0.969), Du4475 (-0.967), MDA-MB-361 (-0.967), NCI-H446 (-0.936), HCA-1 (-0.915), NRH-OS4 (-0.895), RERF-LC-Ad2 (-0.888), MFM-223 (-0.87), OSC-20 (-0.841), KU-19-19 (-0.831).

Literature-anchored findings (GeneRIF, showing 40)

• immunodepletion of Oct-1 and NF-YA proteins or mutations in the OCT-1 and CAAT motifs disrupt BRCA1 binding to the GADD45 promoter (PMID:11777930)
• NF-YA increases during CaCo-2 differentiation and that the constitutive expression of NF-YA, obtained in stably transfected CaCo-2 cells, results in the expression of differentiation markers (PMID:12392713)
• confirms the important transactivating role of NF-YA isoforms for the cystathionine beta synthase 1b promoter via its synergism with Sp1 (PMID:12427542)
• p300 binds to multiple NF-Y trimers to regulate cyclin B2 promoter function (PMID:12482752)
• role in inhibiting von Willebrand factor promoter activation through recruitment of histone deacetylases (PMID:12511565)
• NF-Y is a developmentally regulated inducer of the HOXB4 gene in hematopoietic cells. (PMID:12791656)
• NF-YA is phosphorylated in a pathway involving Cdk2 (PMID:12857729)
• Histone deacetylase inhibitors can induce Gadd45 through its promoter without the need for functional p53, and both Oct-1 and NF-Y concertedly participate in trichostatin A-induced activation of the gadd45 promoter. (PMID:14586402)
• NF-YA has a role in regulating the induction of human OGG1 following administration of DNA-alkylating agents (PMID:14688259)
• p53 negatively regulates Chk2 gene transcription through modulation of NF-Y function and that this regulation may be important for reentry of cells into the cell cycle after DNA damage is repaired. (PMID:15044452)
• NF-Y has a role in regulating EPHX1 expression through its interaction with C/EBPalpha (PMID:15150264)
• transforming growth factor beta type II receptor promoter activity and acetylation of Sp1 by recruitment of PCAF/p300 to a Sp1.NF-Y complex are induced by Trichostatin A (PMID:15647279)
• These results indicate that 1,25(OH)2D3 may affect transcription of the human PTH gene both by competitive binding of VDR and NF-Y, and by modulating transcriptional activity of NF-Y. (PMID:15707954)
• NF-Ya is a potent cellular regulator of hematopoietic stem cell self-renewal (PMID:16081537)
• Data suggest that the cell specifity of HIV-1 expression and replication may be regulated, in part, through the control of TRBP1 expression by NF-Y factors. (PMID:16343534)
• cyclin B2 expression in colorectal adenocarcinoma is dependent on NF-Y (PMID:17289878)
• Our data indicate that multiple CCAAT control elements are involved in the regulation of the SOX3 promoter, suggesting that NF-Y functions as a key regulator of SOX3 gene expression. (PMID:17910945)
• NF-Y is an important mediator of EBV stress response in switching from a latent to lytic state (PMID:18281530)
• p53 overexpression strongly downregulates the transcriptional efficiency driven by an H ferritin promoter construct containing only the NF-Y recognition sequence. (PMID:18372207)
• NF-Y is a fundamental switch at the heart of decision between gene activation and repression in CCAAT regulated genes. (PMID:18446193)
• Transcription factors Sp3, ZBP-89 and NF-Y are capable of binding to the SOX18 promoter region. (PMID:18496767)
• The existence of a functional binding site for the tumor suppressor p53 near the proximal CCAAT box and the fact that the basal expression of annexin A1 in human colon adenocarcinoma cells is driven by p53 at the transcriptional level, is shown. (PMID:18541673)
• Genome-wide occupancy of SREBP1 and its partners NFY and SP1 reveals novel functional roles and combinatorial regulation of distinct classes of genes. (PMID:18654640)
• O-GlcNAc of Sp1 serine/threonine-rich region interrupts a physical interaction between Sp1 and NF-YA, thus inhibiting Sp1-NF-Y cooperative activation of gene transcription. (PMID:19302979)
• review: role of the C/EBPbeta isoforms in breast cancer (PMID:19351437)
• the immediate-early ICP0 gene may be among the first genes to be induced during the early events in HSV-1 reactivation, and NF-Y is important for this induction, and other factors induce the ICP22 promoter. (PMID:19828605)
• The phospho-DeltaNp63alpha forms protein-protein complexes with NF-YA transcription factor regulate the transcription of DDIT3 gene implicated in the programmed cell death of head and neck squamous cell carcinoma cells upon cisplatin exposure. (PMID:20023394)
• A novel mechanism involving coordinated regulation of nuclear levels and acetylation of NF-YA and Bcl6 activates RGS4 transcription. (PMID:20630860)
• Findings establish that NF-Y acts upstream of E2F1 in p53-mediated apoptosis. (PMID:20952509)
• This study unveils a new role for NF-Y in the regulation of human proteasome genes. (PMID:22285817)
• Sp1, CREB, HNF-1, and NF-Y, known to be responsive to hormones and diet, regulate NAGS transcription (PMID:22383952)
• NFYA could be a target of mutant TBP in SCA17. (PMID:22530004)
• NF-Y recruits the developmentally regulated, erythroid transcription activator GATA-2 and general repressor BCL11A to modulate transcription of the gamma-globin gene. (PMID:23071749)
• The crystal structure of NF-Y bound to a 25 bp CCAAT oligonucleotide shows that the histone-fold domains dimer binds to the DNA sugar-phosphate backbone, mimicking the nucleosome H2A/H2B-DNA assembly; NF-YA both binds to NF-YB/NF-YC and inserts an alpha helix deeply into the DNA minor groove, providing sequence-specific contacts to the CCAAT box. (PMID:23332751)
• NF-YA binds directly over the CCAAT sequence. (PMID:23595228)
• Association of p21 with NF-YA suppresses the expression of PLK1 and prevents mitotic death in response to DNA damage. (PMID:24407240)
• Stimulation of the lymphocytes with phytohemagglutinin, restores normal OGG1 levels and repair rates. MAP kinase c-Jun N-terminal kinase (JNK) and the recruitment of the transcription factor NFYA to the promoter region of OGG1 are shown to be involved. (PMID:25463392)
• Data show that Zinc-fingers and homeoboxes 2 (ZHX2) represses nuclear transcription factor Y alpha (NF-Y)-mediated activation of multidrug resistance 1 (MDR1) transcription. (PMID:25473899)
• NF-Y inhibits NT2/D1 cell growth in p53-independent manner and decreases SOX2 expression. (PMID:25756534)
• enhanced CDCA8 promoter activities by NF-Y overexpression and reduced CDCA8 transcription by NF-Y knockdown further verified that NF-Y is a positive regulator of CDCA8 transcription. (PMID:26170459)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfyal	ENSDARG00000001621
danio_rerio	nfya	ENSDARG00000042004
mus_musculus	Nfya	ENSMUSG00000023994
rattus_norvegicus	Nfya	ENSRNOG00000012702
drosophila_melanogaster	Nf-YA	FBGN0035993
caenorhabditis_elegans		WBGENE00011614
caenorhabditis_elegans	nfya-2	WBGENE00043056

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97316) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cell cycle	1
embryonic lethality, complete penetrance	1
decreased fibroblast proliferation	1
increased fibroblast apoptosis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q5E9S2	99.4%	Diamond
Saccharomyces cerevisiae S288C	P06774	82.7%	Diamond
Kluyveromyces lactis NRRL Y-1140	P53768	81.6%	Diamond
Arabidopsis thaliana	Q84JP1	69.5%	Diamond
Schizosaccharomyces pombe 972h-	P24488	67.7%	Diamond
Dictyostelium discoideum	Q54S29	67.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
OARD1	protein-coding	221443
TSPO2	protein-coding	222642
UNC5CL	protein-coding	222643
TREML1	protein-coding	340205
APOBEC2	protein-coding	10930
TREM2	protein-coding	54209
TREML2	protein-coding	79865

Protein

Protein identifiers

Nuclear transcription factor Y subunit alpha — P23511 (reviewed: P23511)

Alternative names: CAAT box DNA-binding protein subunit A, Nuclear transcription factor Y subunit A

All UniProt accessions (3): P23511, A0A0U4C5A9, K9JA49

UniProt curated annotations — full annotation on UniProt →

Function. Component of the sequence-specific heterotrimeric transcription factor (NF-Y) which specifically recognizes a 5’-CCAAT-3’ box motif found in the promoters of its target genes. NF-Y can function as both an activator and a repressor, depending on its interacting cofactors. NF-YA positively regulates the transcription of the core clock component BMAL1.

Subunit / interactions. Heterotrimeric transcription factor composed of three components, NF-YA, NF-YB and NF-YC. NF-YB and NF-YC must interact and dimerize for NF-YA association and DNA binding. Interacts with SP1; the interaction is inhibited by glycosylation of SP1. Interacts with ZHX1. Interacts (via N-terminus) with ZHX2 (via homeobox domain). Interacts with ZFX3.

Subcellular location. Nucleus.

Similarity. Belongs to the NFYA/HAP2 subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
P23511-1	Long	yes
P23511-2	Short

RefSeq proteins (2): NP_002496, NP_068351 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001289	NFYA	Family
IPR018362	CCAAT-binding_factor_CS	Conserved_site

Pfam: PF02045

UniProt features (14 total): helix 3, compositionally biased region 2, chain 1, DNA-binding region 1, turn 1, region of interest 1, short sequence motif 1, modified residue 1, splice variant 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDB	Title	Method	Resolution (Å)
8QU4	NF-YB/C Heterodimer in Complex with a 13-mer NF-YA-derived Peptide Stabilized with …	X-RAY DIFFRACTION	1.38
8QU3	NF-YB/C Heterodimer in Complex with a 13-mer NF-YA-derived Peptide Stabilized with …	X-RAY DIFFRACTION	1.41
8QU2	NF-YB/C Heterodimer in Complex with a 16-mer NF-YA-derived Peptide Stabilized with …	X-RAY DIFFRACTION	1.45
9R4D	NF-YB/C Heterodimer in Complex with NF-YA-derived Stitched Peptide	X-RAY DIFFRACTION	1.7
6QMS	NF-YB/C Heterodimer in Complex with NF-YA-derived Peptide Stabilized with C11-Hydrocarbon …	X-RAY DIFFRACTION	1.8
6QMP	NF-YB/C Heterodimer in Complex with NF-YA Peptide	X-RAY DIFFRACTION	2
6QMQ	NF-YB/C Heterodimer in Complex with NF-YA-derived Peptide Stabilized with C8-Hydrocarbon …	X-RAY DIFFRACTION	2.5
4AWL	The NF-Y transcription factor is structurally and functionally a sequence specific histone	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23511-F1	50.65	0.14

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Other all-alpha-helical DNA-binding domains

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

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 (1)

Type	Positions
Phosphoserine	326

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 19; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

19 pathways:

ID	Pathway	Evidence
R-HSA-1989781	PPARA activates gene expression	curated
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress	electronic
R-HSA-381183	ATF6 (ATF6-alpha) activates chaperone genes	electronic
R-HSA-381033	ATF6 (ATF6-alpha) activates chaperones	—
R-HSA-2426168	Activation of gene expression by SREBF (SREBP)	electronic
R-HSA-8953897	Cellular responses to stimuli	—
R-HSA-2262752	Cellular responses to stress	—
R-HSA-9614085	FOXO-mediated transcription	—
R-HSA-9614657	FOXO-mediated transcription of cell death genes	electronic
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-8957322	Metabolism of steroids	—
R-HSA-381042	PERK regulates gene expression	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)	—
R-HSA-400206	Regulation of lipid metabolism by PPARalpha	—
R-HSA-381119	Unfolded Protein Response (UPR)	—

MSigDB gene sets: 248 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GSE45365_NK_CELL_VS_BCELL_UP, MYAATNNNNNNNGGC_UNKNOWN, MODULE_97, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, TGCGCANK_UNKNOWN, GCM_GSPT1, RORA1_01, CMYB_01, GCM_ZNF198, GEORGES_CELL_CYCLE_MIR192_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_182, TGACCTY_ERR1_Q2

GO Biological Process (6): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), CCAAT-binding factor complex (GO:0016602), protein-DNA complex (GO:0032993), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

14 top-level categories:

Category	Pathways
Unfolded Protein Response (UPR)	2
Metabolism of lipids	2
Regulation of lipid metabolism by PPARalpha	1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1
PERK regulates gene expression	1
ATF6 (ATF6-alpha) activates chaperones	1
FOXO-mediated transcription	1
Metabolism of steroids	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Metabolism	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

31 GO namespaces:

Category	Terms
DNA-templated transcription	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
cellular anatomical structure	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
biological_process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
RNA polymerase II transcription regulator complex	1
protein-containing complex	1
transcription regulator complex	1
nuclear protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
positive regulation of transcription by RNA polymerase II	BP	direct assay
regulation of DNA-templated transcription	BP	direct assay
regulation of transcription by RNA polymerase II	BP	direct assay
CCAAT-binding factor complex	CC	direct assay
RNA polymerase II transcription regulator complex	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
protein-DNA complex	CC	direct assay
DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,644 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFYA	NFYB	P25208	980
NFYA	NFYC	Q13952	979
NFYA	ZHX1	Q9UKY1	901
NFYA	ZHX3	Q9H4I2	847
NFYA	RFX5	P48382	748
NFYA	RFXANK	O14593	682
NFYA	RFXAP	O00287	668
NFYA	MYB	P10242	656
NFYA	RFX1	P22670	627
NFYA	CIITA	P33076	619
NFYA	YY1	P25490	595
NFYA	REPIN1	Q9BWE0	579
NFYA	ATF6B	Q99941	572
NFYA	CREB1	P16220	556
NFYA	SCAP	Q12770	552

IntAct

Human interaction partners of NFYA in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

16 partners by confidence:

Partner	Interaction type	MIscore	Records
NFYC	association	0.850	4
NFYB	physical association	0.840	7
CSNK2A1	physical association	0.670	4
LUC7L2	physical association	0.670	4
APPBP2	physical association	0.620	3
SRSF1	physical association	0.600	3
GTF2A1	physical association	0.560	4
POGZ	physical association	0.560	3
TP53	association	0.540	11
PKM	phosphorylation reaction	0.440	1
ZHX2	physical association	0.400	1
CDC25A	physical association	0.370	1
PAPOLG	physical association	0.370	1
PWP1	physical association	0.370	1
NME2P1	association	0.350	1
SREBF2	physical association	0.000	1

BioGRID (179 interactions; top human partners by supporting records): NFYC (Affinity Capture-MS; 11 records), NFYB (Two-hybrid; 9 records), SP1 (Affinity Capture-Western; 9 records), TP53 (Affinity Capture-Western; 7 records), CDK2 (Affinity Capture-Western; 4 records), CDKN1A (Affinity Capture-Western; 4 records), EP300 (Affinity Capture-Western; 4 records), TOPBP1 (Affinity Capture-Western; 4 records), ZHX1 (Two-hybrid; 4 records), CSNK2A1 (Two-hybrid; 3 records), HMGCS1 (Affinity Capture-MS; 3 records), IRGQ (Affinity Capture-MS; 3 records), NME2P1 (Affinity Capture-MS; 3 records), ACTN4 (Affinity Capture-Western; 2 records), APPBP2 (Two-hybrid; 2 records)

SIGNOR signaling

showing 10 of 11 signaling interactions:

A	Effect	B	Mechanism
RNF4	“up-regulates activity”	NFYA	binding
NFYA	“up-regulates quantity by expression”	GCH1	“transcriptional regulation”
NFYA	“up-regulates quantity by expression”	GFI1B	“transcriptional regulation”
NFYA	“up-regulates quantity by expression”	CBS	“transcriptional regulation”
NFYA	“up-regulates activity”	SP1	binding
NFYA	“up-regulates quantity by expression”	OGG1	“transcriptional regulation”
NFYA	“up-regulates quantity by expression”	SOX18	“transcriptional regulation”
NFYA	“up-regulates quantity by expression”	PHGDH	“transcriptional regulation”
NFYA	“form complex”	NFY	binding
CDK2	“up-regulates activity”	NFYA	phosphorylation

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
p32-CBF-DNA complex	4	C1QBP, NFYA, NFYB, NFYC
CBF-DNA complex	3	NFYA, NFYB, NFYC
NF-YA-LaminA complex	2	LMNA, NFYA

Disease & clinical

Genetic variants

Variant evidence for NFYA: 29 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 42 predictions of 746):

Position(s)	Effect	Δscore	Sites
6:41073085–41073086	donor_loss	1.0000	4
6:41079165–41079166	donor_loss	1.0000	4
6:41084157	donor_gain	1.0000
6:41084193–41084194	donor_loss	1.0000	5
6:41089577–41089578	acceptor_loss	1.0000	6
6:41089711–41089712	donor_loss	1.0000	5
6:41090202–41090203	acceptor_loss	1.0000	6
6:41091695–41091696	donor_loss	1.0000	6
6:41092909	acceptor_gain	1.0000
6:41092910–41092911	acceptor_loss	1.0000	4

AlphaMissense

1,231 missense substitutions predicted likely pathogenic (of 2,244 scored), across 307 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M308	9	0.940	0.999
M238	9	0.857	0.994
H304	8	1.000	1.000
H306	8	1.000	1.000
N268	8	0.999	1.000
H300	8	0.998	1.000
F318	8	0.997	1.000
H273	8	0.990	1.000
I275	7	1.000	1.000
R278	7	1.000	1.000
R279	7	1.000	1.000
E301	7	1.000	1.000
Q271	7	0.999	1.000
E286	7	0.998	1.000
E263	7	0.993	0.998
K270	7	0.979	1.000
I291	7	0.977	1.000
F319	7	0.975	0.996
E262	7	0.974	0.999
E261	7	0.959	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000935

Disease associations

OMIM: gene MIM:189903 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST90002397_156	Mean spheric corpuscular volume	2e-13
GCST004610_69	White blood cell count	2e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, increases abundance, increases expression	2
Benzo(a)pyrene	increases expression	2
Tretinoin	decreases expression, increases expression, affects cotreatment	2
Valproic Acid	increases expression, affects expression	2
Mitomycin	increases expression, affects response to substance	2
Cadmium Chloride	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
deoxynivalenol	increases expression	1
glycidyl methacrylate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases abundance, increases expression	1
nickel chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
coptisine	affects binding, decreases reaction, decreases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Vorinostat	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Benzene	decreases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects binding, increases reaction, increases expression	1
Curcumin	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4P1	SEES3-1V human NFYA, clone1	Embryonic stem cell	Male
CVCL_A4P2	SEES3-1V human NFYA, clone2	Embryonic stem cell	Male
CVCL_A4P3	SEES3-1V human NFYA, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.