POU4F1 (POU class 4 homeobox 1)

2007-12-01   Vishwanie Budhram-Mahadeo , David S Latchman 

Medical Molecular Biology Unit, Institute of Child Health, 30 Guilford St, London WC 1N1 EH, UK





The gene is about 4,468 bases encoded by two exons separated by a short intron.


5, upstream promoter drives expression of longer Brn-3a transcript encoding for Brn-3a(l) protein which includes exons 1 and 2. Regulatory sequences within the intron control expression of short Brn-3a transcript entirely from exon 2, which encodes Brn-3a(s) protein.


Atlas Image
Schematic diagram showing the two isoforms of Brn3-a protein that can be derived from the Brn-3a gene as a result of alternative promoter usage (P1 and P2). AD refers to N-terminal activation domain present only in Brn-3a(l). POU domain found at the C terminal of the protein is common to both Brn-3a(l) and Brn-3a(s).


Protein product for Brn-3a(l) is 423 amino acids with estimated molecular weight of about 42.9 kDa whereas Brn-3a(s) protein is 339 amino acids; about 32 kDa.


Nervous System: Originally isolated from brain cDNA, Brn-3a is expressed in specific neurons of midbrain and hindbrain in CNS and in peripheral sensory neurons (trigeminal ganglia, dorsal root ganglia, spinal cord). It is first seen in neural crest cells that are destined to form sensory neurons and expression persists in mature neurones. Brn-3a is also expressed in retinal ganglion cells and vestibular somatosensory cells, where it cooperates with Brn-3b and Brn-3c respectively to determine cell fate.
Non-neuronal cell: Brn-3a is also expressed in T-cells, heart, testis, ovary, breast epithelium.
Cancers: implicated in neuroblastoma, Ewing sarcoma, cervical cancers, prostate cancers.




Brn-3a proteins act as transcription factors to regulate the expression of target genes, which can alter cell fate. In neuron, Brn-3a protects cells from apoptosis (by transactivating anti-apoptotic genes while repressing expression of pro-apoptotic proteins -see below). Brn-3a also enhances differentiation of neuronal cells in vitro and in-vivo by its ability to transactivate multiple neuronal target promoters. Brn-3a is required for the generation of proprioceptors in trigeminal ganglia.
The POU domain found at the C terminal end of Brn-3a proteins is a bipartite DNA binding domain that can recognize and bind with high affinity and specificity to specific DNA sequences present in the promoters of target genes. DNA consensus sites recognized by Brn-3a include a core A/T rich octamer sequence e.g. ATAATTAAT with the POU-homeodomain (POU-HD) facilitating high affinity binding, whilst the POU-specific (POU-s) domain enhances specificity.
The POU domain of Brn-3a protein also has transactivation function and since Brn-3a(l) and Brn-3a(s) are identical in this region, both proteins can regulate specific subsets of target genes that require POU domain transactivation function e.g. neurofilament, SNAP 25, synaptophysin, Hsp-27. However, some Brn-3a target genes require the N terminal transactivation domain that is found only in Brn-3a(l) protein and therefore these target genes can only be activated by Brn-3a(l) protein e.g. Bcl-2, Bcl-XL, alpha-internexin. Other target genes regulated by Brn-3a include TrkA, neuroD1 and neuroD4, Nav1.7 sodium channel, Doppel glycoprotein, iNOS, p53, NGFI-A, Hsp-27, tyrosine hydroxylase. Brn-3a also auto-regulate its own expression.
In addition to its direct effects on specific target genes, Brn-3a can also alter gene expression by its interaction with other cellular factors. For example, Brn-3a interacts physically with p53 protein, and modifies its effects on specific target genes that regulate cell fate. Thus Brn-3a cooperates with p53 to increase the expression of the cell cycle regulator, p21cip1/waf1 whilst antagonising p53 mediated expression of pro-apoptotic target genes, Bax and Noxa.
Brn-3a other interacting partner includes Rin1 (on target gene, Egr1), HIPK1 (alters TrkA expression), EWS- Fli1 fusion protein (represses Brn-3a mediated effects on survival / differentiation genes).
In addition to cellular target genes, Brn-3a also controls expression of viral genes such as those encoding the human papilloma virus (HPV) immediate early E6/E7 gene (required for HPV transformation of cervical cells) by binding to and transactivating the viral promoter. It is thought that the ability of Brn-3a to transactivate this promoter contributes to its effects in transformation of cervical cancer cells.


High homology with other POU4 family members in the POU domain (C terminal end of the protein), and in the POU4 box (region of homology within the N terminal transactivation domain, present only in Brn-3a(l)). Family members include mammalian POU4f2 (Brn-3b), POU4f3 (Brn-3c), drosophila I-POU and nematode, unc-86.

Implicated in

Entity name
Normal development of sensory neurons in CNS and PNS
Loss of Brn-3a by homologous recombination in mice resulted in significant loss of sensory neurons (e.g. in the midbrain, trigeminal ganglia, dorsal root ganglia) during development. Mutants die within the first day of birth. Studies using cultured neural crest cells demonstrate that Brn-3a expressing cells are destined for sensory lineage. Brn-3a is required for the survival of these cells and achieves this partly by inhibiting expression of p53 mediated, pro-apoptotic target genes. Neural crest cells cultured from Brn-3a knockout mice, undergo significant apoptosis as a result of increased expression of p53 pro-apoptotic target genes, bax and Noxa.
Entity name
Brn-3a mRNA is significantly reduced in neuroblastoma tumour biopsies. Studies undertaken using neuroblastoma cell lines showed that Brn-3a is expressed at low levels when the cells are actively proliferating. However, when cells are induced to cease dividing and undergo differentiation, Brn-3a is significantly increased in cells. Forced over-expression of Brn-3a protects cells from apoptosis but also induces differentiation and neurite outgrowth. Therefore, the significant decrease of Brn-3 in neuroblastoma tumours may contribute to the oncogenic changes in the cells.
Entity name
Neuroendocrine tumours
Brn-3a was shown to be elevated in highly aggressive neuroendocrine tumours SCCL tumours and ACTH producing pituitary tumours.
Entity name
Ewing sarcoma
Brn-3a was detected in some Ewing sarcomas, which are tumours derived from primitive neural ectodermal lineage. These tumours are characterised by rearrangement of genes encoding the Ewing sarcoma (EWS) protein, and members of the Ets family of transcription factors. The most common fusion protein, EWS/Fli1, produces cellular transformation. Brn-3a interacts with the EWS/Fli1 fusion protein, and this interaction prevents Brn-3a mediated transactivation of genes required for cell cycle arrest e.g. p21cip1/waf1 and neurite outgrowth e.g. SNAP-25.
Entity name
Cervical cancer
Brn-3a is expressed at high levels in high-grade cervical intra-epithelial neoplasia (CIN 3) compared to normal cervical biopsies. In this context, Brn-3a may contribute to tissue formation by binding to regulatory regions of Human Papilloma Viruses, HPV-16 and HPV18 and regulate expression of their oncogenic E6 and E7 genes.
Entity name
Prostate cancer
Brn-3a was also detected in prostate cancers with up to 50% of tumours showing significant increase in expression of Brn-3a short isoforms.
Entity name
Systemic lupus erythematosus
Brn-3a is elevated in approximately 43% of patients with SLE and this correlates with enhanced levels of auto-antibodies to the protein. Increased Brn-3a also correlates with enhanced expression of HSP 90 protein in serum of SLE patients.


Pubmed IDLast YearTitleAuthors
82342871993Differential expression of four members of the POU family of proteins in activated and phorbol 12-myristate 13-acetate-treated Jurkat T cells.Bhargava AK et al
124317612002The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells.Budhram-Mahadeo V et al
122031242002The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1).Budram-Mahadeo V et al
161263012005Phosphorylation of the Brn-3a transcription factor is modulated during differentiation and regulates its functional activity.Calissano M et al
13576301992A novel POU homeodomain gene specifically expressed in cells of the developing mammalian nervous system.Collum RG et al
162763512006Brn-3a neuronal transcription factor functional expression in human prostate cancer.Diss JK et al
111604332001Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice.Eng SR et al
152539362004Coordinated regulation of gene expression by Brn3a in developing sensory ganglia.Eng SR et al
110534122001The BRN-3A transcription factor protects sensory but not sympathetic neurons from programmed cell death/apoptosis.Ensor E et al
152723152004Regulation of Hsp27 expression and cell survival by the POU transcription factor Brn3a.Farooqui-Kabir SR et al
151948662004Distinct domains of Brn-3a regulate apoptosis and neurite outgrowth in vivo.Faulkes DJ et al
114292882001Signals from the ventral midline and isthmus regulate the development of Brn3.0-expressing neurons in the midbrain.Fedtsova N et al
86455971995Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors.Fedtsova NG et al
150219032004The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1.Gascoyne DM et al
98788051998Activation of the iNOS gene promoter by Brn-3 POU family transcription factors is dependent upon the octamer motif in the promoter.Gay RD et al
27397231989Expression of a large family of POU-domain regulatory genes in mammalian brain development.He X et al
114935602001Brn3a is a transcriptional regulator of soma size, target field innervation and axon pathfinding of inner ear sensory neurons.Huang EJ et al
103579311999POU domain factor Brn-3a controls the differentiation and survival of trigeminal neurons by regulating Trk receptor expression.Huang EJ et al
155986512005Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate.Hudson CD et al
155320302004Coexpression of Brn-3a POU protein with p53 in a population of neuronal progenitor cells is associated with differentiation and protection against apoptosis.Hudson CD et al
157408072005Effect of Brn-3a deficiency on primary nociceptors in the trigeminal ganglion.Ichikawa H et al
77975901995Regulation of neurite outgrowth and SNAP-25 gene expression by the Brn-3a transcription factor.Lakin ND et al
171965822007Brn3a target gene recognition in embryonic sensory neurons.Lanier J et al
98394401998The Brn-3a transcription factor.Latchman DS et al
89892391997High expression of the POU factor Brn3a in aggressive neuroendocrine tumors.Leblond-Francillard M et al
77338991995Activation of the herpes simplex virus immediate-early gene promoters by neuronally expressed POU family transcription factors.Lillycrop KA et al
88357841996Alternative splicing of the Brn-3a and Brn-3b transcription factor RNAs is regulated in neuronal cells.Liu YZ et al
128105992003Brn3a regulation of TrkA/NGF receptor expression in developing sensory neurons.Ma L et al
124012132002Accessibility of phosphates in domain I of 23 S rRNA in the ribosomal 50 S subunit as detected by R(P) phosphorothioates.Maiväli U et al
89552721996Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons.McEvilly RJ et al
87130671996Differential regulation of neuronal nicotinic acetylcholine receptor subunit gene promoters by Brn-3 POU family transcription factors.Milton NG et al
90375431996Differential regulation of genes encoding synaptic proteins by members of the Brn-3 subfamily of POU transcription factors.Morris PJ et al
115212022001The Brn-3a transcription factor plays a key role in regulating the growth of cervical cancer cells in vivo.Ndisang D et al
162474852006Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a.Ndisang D et al
95414991998The HPV-activating cellular transcription factor Brn-3a is overexpressed in CIN3 cervical lesions.Ndisdang D et al
124339902002Distinct promoter elements mediate the co-operative effect of Brn-3a and p53 on the p21 promoter and their antagonism on the Bax promoter.Perez-Sanchez C et al
158186852005Elevated expression of the Brn-3a and Brn-3b transcription factors in systemic lupus erythematosus correlates with antibodies to Brn-3 and overexpression of Hsp90.Ripley BJ et al
97226271998The N-terminal domain unique to the long form of the Brn-3a transcription factor is essential to protect neuronal cells from apoptosis and for the activation of Bbcl-2 gene expression.Smith MD et al
106406821999Regulation of NGFI-A (Egr-1) gene expression by the POU domain transcription factor Brn-3a.Smith MD et al
87826541996The functionally antagonistic POU family transcription factors Brn-3a and Brn-3b show opposite changes in expression during the growth arrest and differentiation of human neuroblastoma cells.Smith MD et al
112736422001Brn-3a activates the expression of Bcl-x(L) and promotes neuronal survival in vivo as well as in vitro.Smith MD et al
92611451997Coordinate induction of the three neurofilament genes by the Brn-3a transcription factor.Smith MD et al
151479792004EWS differentially activates transcription of the Brn-3a long and short isoform mRNAs from distinct promoters.Thomas GR et al
124322612002The pro-oncoprotein EWS (Ewing's Sarcoma protein) interacts with the Brn-3a POU transcription factor and inhibits its ability to activate transcription.Thomas GR et al
104149831999Autoregulatory sequences are revealed by complex stability screening of the mouse brn-3.0 locus.Trieu M et al
91161901996POU-domain factor expression in the trigeminal ganglion and implications for herpes virus regulation.Turner EE et al
95824311998NT-3 regulates expression of Brn3a but not Brn3b in developing mouse trigeminal sensory neurons.Wyatt S et al
95983661997Role of the Brn-3 family of POU-domain genes in the development of the auditory/vestibular, somatosensory, and visual systems.Xiang M et al

Other Information

Locus ID:

NCBI: 5457
MIM: 601632
HGNC: 9218
Ensembl: ENSG00000152192


dbSNP: 5457
ClinVar: 5457
TCGA: ENSG00000152192


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through Association with Co-factorsREACTOMER-HSA-6804759

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
229307472012Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis.29
150219032004The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1.14
162763512006Brn-3a neuronal transcription factor functional expression in human prostate cancer.12
203760822010POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature.9
236667552013The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival.9
152723152004Regulation of Hsp27 expression and cell survival by the POU transcription factor Brn3a.6
162474852006Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a.4
220643482012AML1/ETO and POU4F1 synergy drives B-lymphoid gene expression typical of t(8;21) acute myeloid leukemia.4
128932012003Measurement of Brn-3a levels in Pap smears provides a novel diagnostic marker for the detection of cervical neoplasia.3
129117302003Detection of cervical neoplasia using measurement of Brn-3a in cervical smears with persistent minor abnormality.2


Vishwanie Budhram-Mahadeo ; David S Latchman

POU4F1 (POU class 4 homeobox 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-12-01

Online version: http://atlasgeneticsoncology.org/gene/44173/pou4f1-(pou-class-4-homeobox-1)