UniProt functional annotation for Q03347



	UniProt functional annotation for Q03347

UniProt code: Q03347.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'- TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (Probable). Essential for the development of normal hematopoiesis. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter. Inhibits KAT6B-dependent transcriptional activation (By similarity). Involved in lineage commitment of immature T cell precursors. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation (PubMed:18258917). CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (PubMed:23481257). Controls the anergy and suppressive function of regulatory T-cells (Treg) by associating with FOXP3. Activates the expression of IL2 and IFNG and down-regulates the expression of TNFRSF18, IL2RA and CTLA4, in conventional T-cells (PubMed:17377532). Positively regulates the expression of RORC in T- helper 17 cells (PubMed:21151104). {ECO:0000250|UniProtKB:Q01196, ECO:0000269|PubMed:17377532, ECO:0000269|PubMed:18258917, ECO:0000269|PubMed:21151104, ECO:0000269|PubMed:23481257, ECO:0000305}.

Function: Isoform 4 shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation. {ECO:0000269|PubMed:11203699}.

Subunit: Heterodimer with CBFB. RUNX1 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization. Interacts with TLE1 and ALYREF/THOC4. Interacts with HIPK2, ELF1, ELF2 and SPI1. Interacts via its Runt domain with the ELF4 N-terminal region. Interaction with ELF2 isoform 2 (NERF-1a) may act to repress RUNX1-mediated transactivation. Interacts with KAT6A and KAT6B. Interacts with SUV39H1, leading to abrogation of transactivating and DNA-binding properties of RUNX1 (By similarity). Interacts with YAP1. Interaction with CDK6 prevents myeloid differentiation, reducing its transcription transactivation activity (By similarity). Found in a complex with PRMT5, RUNX1 and CBFB. Interacts with FOXP3. Interacts with TBX21 (PubMed:21151104). Interacts with DPF2 (By similarity). {ECO:0000250|UniProtKB:Q01196, ECO:0000269|PubMed:11257229, ECO:0000269|PubMed:11375505, ECO:0000269|PubMed:16917507, ECO:0000269|PubMed:17377532, ECO:0000269|PubMed:21151104, ECO:0000269|PubMed:22193545}.

Subcellular location: Nucleus {ECO:0000269|PubMed:17377532}.

Tissue specificity: Isoform 4 is expressed at high levels in thymus, spleen and T-cell lines and at lower levels in myeloid cell lines and nonhematopoietic cells. Isoform 5 is expressed ubiquitously in lumbar vertebrae, brain, kidney, heart, muscle, ovary and osteoblast-like cell line MC3T3-E1.

Developmental stage: Differentially expressed during hematopoietic differentiation. Isoform AML1-B is readily detectable in undifferentiated embryonic stem (es) cells and peak expression is seen on day 6 of differentiation, followed by a gradual decline thereafter. Isoform AML1-C is undetectable in undifferentiated es cells, but is gradually up-regulated along with differentiation and reaches its highest levels on day 8 and this expression is maintained through day 12. Isoform 5 is expressed at high levels at 6-8 dpc and then levels decrease on 12 dpc. Isoform 4 expression is high throughout T-cell development, declines with natural killer cell maturation, and appears to be transiently reduced and then restored during B-cell development.

Domain: A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.

Ptm: Phosphorylated in its C-terminus upon IL-6 treatment. Phosphorylation enhances interaction with KAT6A (By similarity). {ECO:0000250}.

Ptm: Methylated. {ECO:0000250}.

Ptm: Phosphorylated in Ser-249 Thr-273 and Ser-276 by HIPK2 when associated with CBFB and DNA. This phosphorylation promotes subsequent EP300 phosphorylation. {ECO:0000269|PubMed:16917507}.

Disease: Note=Mice with an Runx1 lacking the DNA-binding region are found to die between embryonic days 11.5 to 12.5 due to hemorrhaging in the central nervous system. This hemorrhaging is preceded by necrosis and hematopoiesis is blocked (PubMed:8622955). {ECO:0000269|PubMed:8622955}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'- TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (Probable). Essential for the development of normal hematopoiesis. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter. Inhibits KAT6B-dependent transcriptional activation (By similarity). Involved in lineage commitment of immature T cell precursors. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation (PubMed:18258917). CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (PubMed:23481257). Controls the anergy and suppressive function of regulatory T-cells (Treg) by associating with FOXP3. Activates the expression of IL2 and IFNG and down-regulates the expression of TNFRSF18, IL2RA and CTLA4, in conventional T-cells (PubMed:17377532). Positively regulates the expression of RORC in T- helper 17 cells (PubMed:21151104). {ECO:0000250\|UniProtKB:Q01196, ECO:0000269\|PubMed:17377532, ECO:0000269\|PubMed:18258917, ECO:0000269\|PubMed:21151104, ECO:0000269\|PubMed:23481257, ECO:0000305}.



Function:		Isoform 4 shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation. {ECO:0000269\|PubMed:11203699}.


Subunit:		Heterodimer with CBFB. RUNX1 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization. Interacts with TLE1 and ALYREF/THOC4. Interacts with HIPK2, ELF1, ELF2 and SPI1. Interacts via its Runt domain with the ELF4 N-terminal region. Interaction with ELF2 isoform 2 (NERF-1a) may act to repress RUNX1-mediated transactivation. Interacts with KAT6A and KAT6B. Interacts with SUV39H1, leading to abrogation of transactivating and DNA-binding properties of RUNX1 (By similarity). Interacts with YAP1. Interaction with CDK6 prevents myeloid differentiation, reducing its transcription transactivation activity (By similarity). Found in a complex with PRMT5, RUNX1 and CBFB. Interacts with FOXP3. Interacts with TBX21 (PubMed:21151104). Interacts with DPF2 (By similarity). {ECO:0000250\|UniProtKB:Q01196, ECO:0000269\|PubMed:11257229, ECO:0000269\|PubMed:11375505, ECO:0000269\|PubMed:16917507, ECO:0000269\|PubMed:17377532, ECO:0000269\|PubMed:21151104, ECO:0000269\|PubMed:22193545}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:17377532}.
Tissue specificity:		Isoform 4 is expressed at high levels in thymus, spleen and T-cell lines and at lower levels in myeloid cell lines and nonhematopoietic cells. Isoform 5 is expressed ubiquitously in lumbar vertebrae, brain, kidney, heart, muscle, ovary and osteoblast-like cell line MC3T3-E1.
Developmental stage:		Differentially expressed during hematopoietic differentiation. Isoform AML1-B is readily detectable in undifferentiated embryonic stem (es) cells and peak expression is seen on day 6 of differentiation, followed by a gradual decline thereafter. Isoform AML1-C is undetectable in undifferentiated es cells, but is gradually up-regulated along with differentiation and reaches its highest levels on day 8 and this expression is maintained through day 12. Isoform 5 is expressed at high levels at 6-8 dpc and then levels decrease on 12 dpc. Isoform 4 expression is high throughout T-cell development, declines with natural killer cell maturation, and appears to be transiently reduced and then restored during B-cell development.
Domain:		A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.
Ptm:		Phosphorylated in its C-terminus upon IL-6 treatment. Phosphorylation enhances interaction with KAT6A (By similarity). {ECO:0000250}.
Ptm:		Methylated. {ECO:0000250}.
Ptm:		Phosphorylated in Ser-249 Thr-273 and Ser-276 by HIPK2 when associated with CBFB and DNA. This phosphorylation promotes subsequent EP300 phosphorylation. {ECO:0000269\|PubMed:16917507}.
Disease:		Note=Mice with an Runx1 lacking the DNA-binding region are found to die between embryonic days 11.5 to 12.5 due to hemorrhaging in the central nervous system. This hemorrhaging is preceded by necrosis and hematopoiesis is blocked (PubMed:8622955). {ECO:0000269\|PubMed:8622955}.