Biology:BCL11A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

B-cell lymphoma/leukemia 11A is a protein that in humans is encoded by the BCL11A gene.[1][2][3]

Function

The BCL11A 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.[3] The protein associates with the SWI/SNF complex, that regulates gene expression via chromatin remodeling.[4]

BCL11A is highly expressed in several hematopoietic lineages, and plays a role in the switch from γ- to β-globin expression during the fetal to adult erythropoiesis transition.[5]

Furthermore, BCL11A is expressed in the brain, where it forms a protein complex with CASK to regulate axon outgrowth and branching.[6] In the neocortex, BCL11A binds to the TBR1 regulatory region and inhibits the expression of TBR1.[7]

Clinical significance

The corresponding Bcl11a mouse gene is a common site of retroviral integration in myeloid 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 increasing fetal hemoglobin production in diseases such as beta thalassemia and sickle cell anemia by inhibiting BCL11A are currently being explored.[8][9]

Furthermore, heterozygous de novo mutations in BCL11A have been identified in an intellectual disability disorder, accompanied with global developmental delay and autism spectrum disorder.[10] 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.[11][12]

Interactions

BCL11A has been shown to interact with a number of proteins. BCL11A was initially discovered as a COUP-TFI interacting protein.[13] In the nucleus, BCL11A forms paraspeckles that co-localize with NONO.[10] In neurons, BCL11A interacts with CASK to regulate target genes.[6] Furthermore, BCL11A interacts with the neuron-specific protein TBR1, which is also implicated in intellectual disability and autism spectrum disorder.[14]

References

  1. ↑ "The BCL11 gene family: involvement of BCL11A in lymphoid malignancies". Blood 98 (12): 3413–20. December 2001. doi:10.1182/blood.V98.12.3413. PMID 11719382. 
  2. ↑ "Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia". Proceedings of the National Academy of Sciences of the United States of America 105 (5): 1620–5. February 2008. doi:10.1073/pnas.0711566105. PMID 18245381. Bibcode: 2008PNAS..105.1620U. 
  3. ↑ 3.0 3.1 "Entrez Gene: BCL11A B-cell CLL/lymphoma 11A (zinc finger protein)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=53335. 
  4. ↑ "Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy". Nature Genetics 45 (6): 592–601. June 2013. doi:10.1038/ng.2628. PMID 23644491. 
  5. ↑ "Bcl11a erythroid enhancer". Blood 128 (19): 2338–2342. November 2016. doi:10.1182/blood-2016-08-736249. PMID 27707736. 
  6. ↑ 6.0 6.1 "X-linked mental retardation gene CASK interacts with Bcl11A/CTIP1 and regulates axon branching and outgrowth" (in de). Journal of Neuroscience Research 88 (11): 2364–73. August 2010. doi:10.1002/jnr.22407. PMID 20623620. 
  7. ↑ "The Specification of Cortical Subcerebral Projection Neurons Depends on the Direct Repression of TBR1 by CTIP1/BCL11a". The Journal of Neuroscience 35 (19): 7552–64. May 2015. doi:10.1523/JNEUROSCI.0169-15.2015. PMID 25972180. 
  8. ↑ Zipkin, Mark (2019-12-06). "CRISPR's "magnificent moment" in the clinic" (in en). Nature Biotechnology. doi:10.1038/d41587-019-00035-2. PMID 33277639. https://www.nature.com/articles/d41587-019-00035-2. 
  9. ↑ "Sickle cell: 'The revolutionary gene-editing treatment that gave me new life'" (in en-GB). BBC News. 2022-02-20. https://www.bbc.com/news/health-60348497. 
  10. ↑ 10.0 10.1 "BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription". American Journal of Human Genetics 99 (2): 253–74. August 2016. doi:10.1016/j.ajhg.2016.05.030. PMID 27453576. 
  11. ↑ "Discovering human diabetes-risk gene function with genetics and physiological assays". Nature Communications 9 (1): 3855. September 2018. doi:10.1038/s41467-018-06249-3. PMID 30242153. Bibcode: 2018NatCo...9.3855P. 
  12. ↑ "BCL11A gene DNA methylation contributes to the risk of type 2 diabetes in males". Experimental and Therapeutic Medicine 8 (2): 459–463. August 2014. doi:10.3892/etm.2014.1783. PMID 25009601. 
  13. ↑ "COUP-TF (chicken ovalbumin upstream promoter transcription factor)-interacting protein 1 (CTIP1) is a sequence-specific DNA binding protein". The Biochemical Journal 368 (Pt 2): 555–63. December 2002. doi:10.1042/bj20020496. PMID 12196208. 
  14. ↑ "Functional characterization of TBR1 variants in neurodevelopmental disorder". Scientific Reports 8 (1): 14279. September 2018. doi:10.1038/s41598-018-32053-6. PMID 30250039. Bibcode: 2018NatSR...814279D. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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