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BCL11A

BCL11A
Identifiers
AliasesBCL11A, BCL11A-L, BCL11A-S, BCL11A-XL, BCL11a-M, CTIP1, EVI9, HBFQTL5, ZNF856, B-cell CLL/lymphoma 11A, DILOS, B cell CLL/lymphoma 11A, BAF complex component, BAF chromatin remodeling complex subunit SMARCM1
External IDsOMIM: 606557; MGI: 106190; HomoloGene: 11284; GeneCards: BCL11A; OMA:BCL11A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

53335

14025

Ensembl

ENSG00000119866

ENSMUSG00000000861

UniProt

Q9H165

Q9QYE3

RefSeq (mRNA)

NM_001159289
NM_001159290
NM_001242934
NM_016707

RefSeq (protein)

NP_060484
NP_075044
NP_612569
NP_001350793
NP_001352538

NP_001152761
NP_001152762
NP_001229863
NP_057916

Location (UCSC)Chr 2: 60.45 – 60.55 MbChr 11: 24.08 – 24.17 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

B-cell lymphoma/leukemia 11A is a protein that in humans is encoded by the BCL11A gene.[5][6][7]

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.[7] The protein associates with the SWI/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 from γ- to β-globin expression during the fetal to adult erythropoiesis 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 the neocortex, BCL11A binds to the TBR1 regulatory region and inhibits the expression of TBR1.[11]

Tetramerization of BCL11A shields it from proteasomal degradation and is critical for its γ-globin repression activity.[12]

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.[13][14]

Furthermore, heterozygous de novo mutations in BCL11A have been identified in an intellectual disability disorder, accompanied with global developmental delay and autism 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]

Interactions

BCL11A has been shown to interact with a number of proteins. BCL11A was initially discovered as a COUP-TFI interacting protein.[18] In the nucleus, BCL11A forms paraspeckles that co-localize with NONO.[15] In neurons, BCL11A interacts with CASK to regulate target genes.[10] Furthermore, BCL11A interacts with the neuron-specific protein TBR1, which is also implicated in intellectual disability and autism spectrum disorder.[19]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000119866 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000861 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, et al. (December 2001). "The BCL11 gene family: involvement of BCL11A in lymphoid malignancies". Blood. 98 (12): 3413–20. doi:10.1182/blood.V98.12.3413. PMID 11719382.
  6. ^ Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, et al. (February 2008). "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. Bibcode:2008PNAS..105.1620U. doi:10.1073/pnas.0711566105. PMC 2234194. PMID 18245381.
  7. ^ a b "Entrez Gene: BCL11A B-cell CLL/lymphoma 11A (zinc finger protein)".
  8. ^ Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, et al. (June 2013). "Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy". Nature Genetics. 45 (6): 592–601. doi:10.1038/ng.2628. PMC 3667980. PMID 23644491.
  9. ^ Smith EC, Luc S, Croney DM, Woodworth MB, Greig LC, Fujiwara Y, et al. (November 2016). "Bcl11a erythroid enhancer". Blood. 128 (19): 2338–2342. doi:10.1182/blood-2016-08-736249. PMC 5106112. PMID 27707736.
  10. ^ a b Kuo 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. PMID 20623620. S2CID 19810502.
  11. ^ Cánovas J, Berndt FA, Sepúlveda H, Aguilar R, Veloso FA, Montecino M, et al. (May 2015). "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. doi:10.1523/JNEUROSCI.0169-15.2015. PMC 6705430. PMID 25972180.
  12. ^ Zheng G, Yin M, Mehta S, Chu IT, Wang S, AlShaye A, et al. (2024-11-29). "A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing". Science. 386 (6725): 1010–1018. doi:10.1126/science.adp3025.
  13. ^ Zipkin M (December 2019). "CRISPR's "magnificent moment" in the clinic". Nature Biotechnology. doi:10.1038/d41587-019-00035-2. PMID 33277639. S2CID 213060203.
  14. ^ "Sickle cell: 'The revolutionary gene-editing treatment that gave me new life'". BBC News. 2022-02-20. Retrieved 2023-03-27.
  15. ^ a b Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, et al. (August 2016). "BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription". American Journal of Human Genetics. 99 (2): 253–74. doi:10.1016/j.ajhg.2016.05.030. PMC 4974071. PMID 27453576.
  16. ^ Peiris H, Park S, Louis S, Gu X, Lam JY, Asplund O, et al. (September 2018). "Discovering human diabetes-risk gene function with genetics and physiological assays". Nature Communications. 9 (1): 3855. Bibcode:2018NatCo...9.3855P. doi:10.1038/s41467-018-06249-3. PMC 6155000. PMID 30242153.
  17. ^ Tang L, Wang L, Ye H, Xu X, Hong Q, Wang H, et al. (August 2014). "BCL11A gene DNA methylation contributes to the risk of type 2 diabetes in males". Experimental and Therapeutic Medicine. 8 (2): 459–463. doi:10.3892/etm.2014.1783. PMC 4079426. PMID 25009601.
  18. ^ Avram D, Fields A, Senawong T, Topark-Ngarm A, Leid M (December 2002). "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. doi:10.1042/bj20020496. PMC 1223006. PMID 12196208.
  19. ^ den Hoed J, Sollis E, Venselaar H, Estruch SB, Deriziotis P, Fisher SE (September 2018). "Functional characterization of TBR1 variants in neurodevelopmental disorder". Scientific Reports. 8 (1): 14279. Bibcode:2018NatSR...814279D. doi:10.1038/s41598-018-32053-6. PMC 6155134. PMID 30250039.

Further reading

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

Quelle: https://en.wikipedia.org/wiki/BCL11A