BMI1 (BMI1 polycomb ring finger oncogene)

Alias_names	PCGF4
	polycomb group ring finger 4
	B lymphoma Mo-MLV insertion region 1 homolog (mouse)
Alias_symbol (synonym)	RNF51
Other alias	MGC12685
	flvi-2/bmi-1
HGNC (Hugo)	BMI1
LocusID (NCBI)	648
Atlas_Id	807
Location	10p12.2  [Link to chromosome band 10p12]
Location_base_pair	Starts at 22321210 and ends at 22331485 bp from pter ( according to hg19-Feb_2009)  [Mapping BMI1.png]
Local_order	MLLT10 gene is one of the neighboring genes of BMI1. It locates 786566 base pairs downstream from the start site of BMI1. MLLT10 or AF10 is a transcription factor which is also one of the fusion proteins of ALL. ALL-AF10 can result in the development of T-cell ALL, AML FAB 0, AML FAB 1, AML FAB 5 and AML FAB 7. PIP4K2A is the gene for Phosphatidylinositol-4-phosphate 5-kinase. The protein transcribed from this gene is catalyzing the phosphorylation of phosphatidylinositol-5-phosphate on the fourth hydroxyl of the myo-inositol ring to form phosphatidylinositol-5,4-bisphosphate. Phosphatidylinositol-5,4-bisphosphate is a precursor to second messengers in the phosphoinositide signal transduction pathways and it is involved in the regulation of secretion, cell proliferation, differentiation and motility.

Description	DNA size: 10.04 kb with 10 exons. The BMI1 gene is a highly conserved gene. The cDNA shows 86% identity to the mouse sequence.
Transcription	mRNA size: 3199 bp.

Note	326 amino acids Molecular weight of the protein: 36949 Da.
Description	The ring finger domain is a cysteine-rich domain that binds two atoms of zinc and plays a key role in the process of ubiquitination. In hematopoietic stem cells BMI1 interacts with a proliferation inhibitor E4F through the IE4F site.
Expression	Hematopoietic system: BMI1 is expressed in adult and embryonic fetal liver hematopoietic stem cells (HSC). During hematopoietic development the expression of BMI1 declines. Bmi1-/- mice are born with a hypocellular bone marrow, they have normal number of myeloid cells in the peripheral blood but lower number of lymphocytes. In the bone marrow of Bmi1-/- mice the total HSC number is decreased with 10-fold and transplanted bone marrow and fetal liver cells were able to contribute to hematopoiesis only transiently. Bmi1-depleted mice die within two months after birth. Adult HSCs from Bmi1-/- mice lack self-renewal potential. Furthermore, expression of stem cell-associated genes, cell survival genes, transcription factors and genes modulating proliferation was altered in the bone marrow cells. BMI1 overexpression was studied in transgenic mice and human CB models. In these mouse models 14% of the mice developed lymphoma. BMI1 overexpression in CD34+ cord blood cells resulted in long term maintenance and self-renewal of human hematopoietic stem and progenitor cells. These cells engrafted more efficiently in NOD-SCID mice and gave a rise to secondary engraftment. Nervous system: BMI1 is required for neural stem cell self-renewal but it does not influence their survival and differentiation. BMI1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. The absence of BMI1 was related to the low level of p16 Ink4 as well as to low proliferation rate of neural stem cells. BMI1-deficient mice develop balance disorders, tremor, behavior disorders and they have a severe reduction in total postnatal brain mass. Fibroblasts: In BMI1-deficient primary mouse embryonic fibroblast cell cycle progression to S phase was impaired and cells entered early senescence.
Localisation	In nucleus and in the cytoplasm.
Function	BMI1 is a member of the Polycomb group (PcG) genes, which are transcriptional repressors that play essential roles in the maintenance of appropriate gene expression during development. Two distinct multiprotein PcG complexes have been identified, the Polycomb Repression Complex (PRC) 1 and PRC2. The PRC2 complex is involved in initiation of silencing and contains histone deacetylases and methyltransferases that can methylate H3 lysine 9 and 27 (H3K27). Deletion of PRC2 genes in mice results in embryonic lethality, emphasizing their importance in development. PRC1 is implicated in stable maintenance of gene repression and recognizes the methylation marks set by PRC2. Mice mutant for most PRC1 genes survive until birth as result of partial functional redundancy provided by their homologues, but developmental defects do arise thereafter as is e.g. the case in the hematopoietic compartment after deletion of BMI1. Targeted deletion of BMI1 has shown that although the numbers of fetal liver-derived HSCs is normal in these mice, their proliferative and self-renewal capacity is severely impaired. In adult BMI1-deficient mice, the HSCs are less frequent and display an impaired competitive repopulation capacity. Gain-of-function studies demonstrated enhanced self-renewal of murine HSC and with a shift in balance towards more symmetric stem cell divisions. Constitutive expression of BMI1 in human cord blood cells results in prolonged maintenance of the stem cell pool and enhances self-renewal of human stem and progenitor cells. BMI1 is potent negative regulator of the Ink4a/Arf locus in embryonic fibroblasts. This locus encodes the cell cycle regulators and tumor suppressor p16 and p19/p14. Increased expression of these genes was observed in the BMI1-deficient mice. However, INK4A/ARF-independent BMI1-targets must exist as well since overexpression of BMI1 in p16/p19-deficient cells still altered HSC self-renewal phenotypes.

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