BCL11A explained

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]

Tetramerization of BCL11A shields it from proteasomal degradation and is critical for its γ-globin repression activity.^[8]

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.^{[9] [10]}

Furthermore, heterozygous de novo mutations in BCL11A have been identified in an intellectual disability disorder, accompanied with global developmental delay and autism spectrum disorder.^[11] 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.^{[12] [13]}

Interactions

BCL11A has been shown to interact with a number of proteins. BCL11A was initially discovered as a COUP-TFI interacting protein.^[14] In the nucleus, BCL11A forms paraspeckles that co-localize with NONO. In neurons, BCL11A interacts with CASK to regulate target genes. Furthermore, BCL11A interacts with the neuron-specific protein TBR1, which is also implicated in intellectual disability and autism spectrum disorder.^[15]

Further reading

• Toward a complete human genome sequence . Genome Research . 8 . 11 . 1097–108 . November 1998 . 9847074 . 10.1101/gr.8.11.1097 . The Sanger Centre . The Washington University Genome Sequencing Cente . free .
• Avram D, Fields A, Pretty On Top K, Nevrivy DJ, Ishmael JE, Leid M . Isolation of a novel family of C(2)H(2) zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors . The Journal of Biological Chemistry . 275 . 14 . 10315–22 . April 2000 . 10744719 . 2819356 . 10.1074/jbc.275.14.10315 . free .
• Nakamura T, Yamazaki Y, Saiki Y, Moriyama M, Largaespada DA, Jenkins NA, Copeland NG . Evi9 encodes a novel zinc finger protein that physically interacts with BCL6, a known human B-cell proto-oncogene product . Molecular and Cellular Biology . 20 . 9 . 3178–86 . May 2000 . 10757802 . 85612 . 10.1128/MCB.20.9.3178-3186.2000 .
• Saiki Y, Yamazaki Y, Yoshida M, Katoh O, Nakamura T . 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 . December 2000 . 11161790 . 10.1006/geno.2000.6385 .
• Nagase T, Nakayama M, Nakajima D, Kikuno R, Ohara O . Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 8 . 2 . 85–95 . April 2001 . 11347906 . 10.1093/dnares/8.2.85 . free .
• Martín-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B, Grote W, Novo FJ, Calasanz MJ, Hansmann ML, Dyer MJ, Siebert R . Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma . Blood . 99 . 4 . 1474–7 . February 2002 . 11830502 . 10.1182/blood.V99.4.1474 . free .
• Küppers R, Sonoki T, Satterwhite E, Gesk S, Harder L, Oscier DG, Tucker PW, Dyer MJ, Siebert R . Lack of somatic hypermutation of IG V(H) genes in lymphoid malignancies with t(2;14)(p13;q32) translocation involving the BCL11A gene . Leukemia . 16 . 5 . 937–9 . May 2002 . 11986957 . 10.1038/sj.leu.2402480 . free .
• Senawong T, Peterson VJ, Leid M . BCL11A-dependent recruitment of SIRT1 to a promoter template in mammalian cells results in histone deacetylation and transcriptional repression . Archives of Biochemistry and Biophysics . 434 . 2 . 316–25 . February 2005 . 15639232 . 2819353 . 10.1016/j.abb.2004.10.028 .
• Liu H, Ippolito GC, Wall JK, Niu T, Probst L, Lee BS, Pulford K, Banham AH, Stockwin L, Shaffer AL, Staudt LM, Das C, Dyer MJ, Tucker PW . Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells . Molecular Cancer . 5 . 18 . May 2006 . 16704730 . 1526750 . 10.1186/1476-4598-5-18 . free .
• Weniger MA, Pulford K, Gesk S, Ehrlich S, Banham AH, Lyne L, Martin-Subero JI, Siebert R, Dyer MJ, Möller P, Barth TF . Gains of the proto-oncogene BCL11A and nuclear accumulation of BCL11A(XL) protein are frequent in primary mediastinal B-cell lymphoma . Leukemia . 20 . 10 . 1880–2 . October 2006 . 16871282 . 10.1038/sj.leu.2404324 . free .
• Szafranski K, Schindler S, Taudien S, Hiller M, Huse K, Jahn N, Schreiber S, Backofen R, Platzer M . Violating the splicing rules: TG dinucleotides function as alternative 3' splice sites in U2-dependent introns . Genome Biology . 8 . 8 . R154 . 2007 . 17672918 . 2374985 . 10.1186/gb-2007-8-8-r154 . free .

Notes and References

1. Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ . The BCL11 gene family: involvement of BCL11A in lymphoid malignancies . Blood . 98 . 12 . 3413–20 . December 2001 . 11719382 . 10.1182/blood.V98.12.3413 . free .
2. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A . 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 . 18245381 . 2234194 . 10.1073/pnas.0711566105 . 2008PNAS..105.1620U . free .
3. Web site: Entrez Gene: BCL11A B-cell CLL/lymphoma 11A (zinc finger protein).
4. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR . Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy . Nature Genetics . 45 . 6 . 592–601 . June 2013 . 23644491 . 3667980 . 10.1038/ng.2628 .
5. Smith EC, Luc S, Croney DM, Woodworth MB, Greig LC, Fujiwara Y, Nguyen M, Sher F, Macklis JD, Bauer DE, Orkin SH . Bcl11a erythroid enhancer . Blood . 128 . 19 . 2338–2342 . November 2016 . 27707736 . 5106112 . 10.1182/blood-2016-08-736249 .
6. Kuo TY, Hong CJ, Chien HL, Hsueh YP . X-linked mental retardation gene CASK interacts with Bcl11A/CTIP1 and regulates axon branching and outgrowth . de . Journal of Neuroscience Research . 88 . 11 . 2364–73 . August 2010 . 20623620 . 10.1002/jnr.22407 . 19810502 .
7. Cánovas J, Berndt FA, Sepúlveda H, Aguilar R, Veloso FA, Montecino M, Oliva C, Maass JC, Sierralta J, Kukuljan M . 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 . 25972180 . 6705430 . 10.1523/JNEUROSCI.0169-15.2015 .
8. Zheng . Ge . Yin . Maolu . Mehta . Stuti . Chu . I-Te . Wang . Stacy . AlShaye . Alia . Drainville . Kirstin . Buyanbat . Altantsetseg . Bienfait . Frédérique . Tenglin . Karin . Zhu . Qian . Orkin . Stuart H. . 2024-11-29 . A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing . Science . 386 . 6725 . 1010–1018 . 10.1126/science.adp3025.
9. Zipkin M . CRISPR's "magnificent moment" in the clinic . Nature Biotechnology . December 2019 . 33277639 . 10.1038/d41587-019-00035-2 . 213060203 .
10. News: 2022-02-20 . Sickle cell: 'The revolutionary gene-editing treatment that gave me new life' . en-GB . BBC News . 2023-03-27.
11. Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, Joss SK, Holder SE, Morton JE, Turner C, Thevenon J, Mellul K, Sánchez-Andrade G, Ibarra-Soria X, Deriziotis P, Santos RF, Lee SC, Faivre L, Kleefstra T, Liu P, Hurles ME, Fisher SE, Logan DW . BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription . American Journal of Human Genetics . 99 . 2 . 253–74 . August 2016 . 27453576 . 4974071 . 10.1016/j.ajhg.2016.05.030 .
12. Peiris H, Park S, Louis S, Gu X, Lam JY, Asplund O, Ippolito GC, Bottino R, Groop L, Tucker H, Kim SK . Discovering human diabetes-risk gene function with genetics and physiological assays . Nature Communications . 9 . 1 . September 2018 . 3855 . 10.1038/s41467-018-06249-3. 30242153 . 6155000 . 2018NatCo...9.3855P . free .
13. Tang L, Wang L, Ye H, Xu X, Hong Q, Wang H, Xu L, Bu S, Zhang L, Cheng J, Liu P, Ye M, Mai Y, Duan S . BCL11A gene DNA methylation contributes to the risk of type 2 diabetes in males . Experimental and Therapeutic Medicine . 8 . 2 . 459–463 . August 2014 . 25009601 . 10.3892/etm.2014.1783 . 4079426 . free .
14. Avram D, Fields A, Senawong T, Topark-Ngarm A, Leid M . 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 . 12196208 . 1223006 . 10.1042/bj20020496 .
15. den Hoed J, Sollis E, Venselaar H, Estruch SB, Deriziotis P, Fisher SE . Functional characterization of TBR1 variants in neurodevelopmental disorder . Scientific Reports . 8 . 1 . 14279 . September 2018 . 30250039 . 6155134 . 10.1038/s41598-018-32053-6 . 2018NatSR...814279D .