TheBCL11A gene encodes for a regulatory C2H2 type zinc-finger protein, that can bind to the DNA. Five alternatively spliced transcript variants of this gene, which encode distinct isoforms, have been reported.[7] The protein associates with theSWI/SNF complex, that regulates gene expression via chromatin remodeling.[8]
BCL11A is highly expressed in several hematopoietic lineages, and plays a role in the switch fromγ- to β-globin expression during the fetal to adulterythropoiesis transition.[9]
Furthermore, BCL11A is expressed in the brain, where it forms a protein complex with CASK to regulate axon outgrowth and branching.[10] In theneocortex, BCL11A binds to theTBR1 regulatory region and inhibits the expression ofTBR1.[11]
Tetramerization of BCL11A shields it from proteasomal degradation and is critical for its γ-globin repression activity.[12]
The correspondingBcl11a mouse gene is a common site ofretroviral integration inmyeloid leukemia, and may function as a leukemia disease gene, in part, through its interaction with BCL6. During hematopoietic cell differentiation, this gene is down-regulated. It is possibly involved in lymphoma pathogenesis since translocations associated with B-cell malignancies also deregulates its expression. In addition, BCL11A has been found to play a role in the suppression of fetal hemoglobin production. Therapeutic strategies aimed at increasingfetal hemoglobin production in diseases such asbeta thalassemia andsickle cell anemia by inhibiting BCL11A are currently being explored.[13][14]
Furthermore, heterozygousde novo mutations inBCL11A have been identified in anintellectual disability disorder, accompanied with global developmental delay andautism spectrum disorder.[15] These mutations disrupt BCL11A homodimerization and transcriptional regulation.
BCL11A has also been identified as an important gene of interest in type-2 diabetes. Methylation of BCl11A has been hypothesized to contribute to type-2 diabetes risk, while BCL11a loss in a human islet model was demonstrated to result in an increase in insulin secretion.[16][17]
BCL11A has been shown to interact with a number of proteins. BCL11A was initially discovered as aCOUP-TFI interacting protein.[18] In the nucleus, BCL11A forms paraspeckles that co-localize withNONO.[15] In neurons, BCL11A interacts withCASK to regulate target genes.[10] Furthermore, BCL11A interacts with the neuron-specific proteinTBR1, which is also implicated in intellectual disability and autism spectrum disorder.[19]
^abKuo TY, Hong CJ, Chien HL, Hsueh YP (August 2010). "X-linked mental retardation gene CASK interacts with Bcl11A/CTIP1 and regulates axon branching and outgrowth".Journal of Neuroscience Research (in German).88 (11):2364–73.doi:10.1002/jnr.22407.PMID20623620.S2CID19810502.
^Zheng G, Yin M, Mehta S, Chu IT, Wang S, AlShaye A, et al. (November 2024). "A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing".Science.386 (6725):1010–1018.Bibcode:2024Sci...386.1010Z.doi:10.1126/science.adp3025.PMID39607926.{{cite journal}}: CS1 maint: overridden setting (link)
Saiki Y, Yamazaki Y, Yoshida M, Katoh O, Nakamura T (December 2000). "Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells".Genomics.70 (3):387–91.doi:10.1006/geno.2000.6385.PMID11161790.
