Biology:IKZF1

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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

DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene.[1][2][3]

Ikaros - transcription factor

Ikaros is a transcription factor that is encoded by the IKZF genes of the Ikaros family zinc finger group. Zinc finger is a small structural motif of protein that allows protein binding to DNA or RNA molecule that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold.

Ikaros displays crucial functions in the hematopoietic system and is a known regulator of immune cells development, mainly in early B cells, CD4+ T cells. Its dysfunction has been linked to the development of chronic lymphocytic leukemia.[4][5] In particular, Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia[4] and that it also has a part in the differentiation and function of individual T helper cells.[6]

Ikaros also has a role during the later stages of B cell development during VDJ recombination in switch class of the antibody isotypes and expression of the B cell receptor.[7]

In Ikaros knockout mice, T cells but not B cells are generated late in mouse development due to late compensatory expression of the related gene Aiolos (IKZF3).[8] Ikaros point mutant mice are embryonic lethal due to anemia; they have severe defects in terminal erythrocyte and granulocyte differentiation, and excessive macrophage formation.[9] SNPs located near the 3' region of IKZF1 in humans have been linked to susceptibility to childhood acute lymphoblastic leukemia (ALL)[10] as well as type 1 diabetes.[11] The two effects appear to be in opposite directions, with the allele marking susceptibility to ALL protecting from T1D and vice versa.[11]

Further evidence shows that Ikaros regulates the development of medullary thymic epithelial cells (mTECs). Conditional deletion of Ikzf1 in thymic epithelial cells by Foxn1-Cre in mice, results in the dysregulation of various mTEC subsets, including the loss of Aire+ mTECs. The loss of Aire (Autoimmune regulator) expressing mTECs also causes global loss of tissue restricted antigens (TRAs) and Aire-dependent mimetic cell populations, with the loss of TRAs eventually leading to breakdown of immune tolerance.[12]

Genes of the Ikaros Zinc Finger Family group

The Ikaros Zinc Finger (IkZF) family of transcription factors are known regulators of hematopoietic cell development and many immune cells including that of CD4+ T cells.

The IkZF family consists of five members: Ikaros (encoded by the gene Ikzf1), Helios (Ikzf2), Aiolos (Ikzf3), Eos (Ikzf4), and Pegasus (Ikzf5). These factors contain N-terminal zinc finger (ZF) domains, which are responsible for mediating direct interactions with DNA, and C-terminal ZFs, which facilitate homo- and heterodimerization between IkZF family members. [13]

IKZF1 is upregulated in granulocytes, B cells, CD4 and CD8 T cells, and NK cells, and downregulated in erythroblasts, megakaryocytes and monocytes.[14]

Ikaros deficiency

The mutation in the IKZF1 gene can cause dysfunction of the Ikaros transcription factor. The dysfunction affects expression in B cells that can lead to deregulation of the BCR signaling during B cell development and is associated with B cell transformation. The deregulation then can result in low proliferation rate and increased apoptosis of the B cells. The deregulation may be related with lymphoproliferative disorders and different forms of leukemia. [15]

Interactions

IKZF1 has been shown to interact with:


References

  1. ↑ "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment". Science 258 (5083): 808–12. October 1992. doi:10.1126/science.1439790. PMID 1439790. Bibcode: 1992Sci...258..808G. 
  2. ↑ "The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene". Molecular and Cellular Biology 14 (11): 7111–23. November 1994. doi:10.1128/mcb.14.11.7111. PMID 7935426. 
  3. ↑ "Entrez Gene: IKZF1 IKAROS family zinc finger 1 (Ikaros)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10320. 
  4. ↑ 4.0 4.1 "Role of Ikaros in T-cell acute lymphoblastic leukemia". World Journal of Biological Chemistry 2 (6): 108–14. June 2011. doi:10.4331/wjbc.v2.i6.108. PMID 21765975. 
  5. ↑ "Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia". Journal of Leukocyte Biology 106 (3): 581–594. July 2019. doi:10.1002/JLB.MA1118-454R. PMID 31299112. 
  6. ↑ "+ T Helper Cell Differentiation". Frontiers in Immunology 10: 1299. 2019. doi:10.3389/fimmu.2019.01299. PMID 31244845. 
  7. ↑ "Ikaros in B cell development and function". World Journal of Biological Chemistry 2 (6): 132–9. June 2011. doi:10.4331/wjbc.v2.i6.132. PMID 21765979. 
  8. ↑ "The role of the Ikaros gene in lymphocyte development and homeostasis". Annual Review of Immunology 15: 155–76. 1997. doi:10.1146/annurev.immunol.15.1.155. PMID 9143685. 
  9. ↑ "Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor". Immunity 19 (1): 131–44. July 2003. doi:10.1016/s1074-7613(03)00168-7. PMID 12871645. 
  10. ↑ "Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia". Nature Genetics 41 (9): 1006–10. September 2009. doi:10.1038/ng.430. PMID 19684604. 
  11. ↑ 11.0 11.1 "An allele of IKZF1 (Ikaros) conferring susceptibility to childhood acute lymphoblastic leukemia protects against type 1 diabetes". Diabetes 60 (3): 1041–4. March 2011. doi:10.2337/db10-0446. PMID 21270240. 
  12. ↑ Sin, Jun Hyung; Sucharov, Juliana; Kashyap, Sujit; Wang, Yi; Proekt, Irina; Liu, Xian; Parent, Audrey V.; Gupta, Alexander et al. (2023-10-27). "Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance". Science Immunology 8 (88): eabq3109. doi:10.1126/sciimmunol.abq3109. ISSN 2470-9468. PMID 37889983. https://pubmed.ncbi.nlm.nih.gov/37889983. 
  13. ↑ "+ T Helper Cell Differentiation". Frontiers in Immunology 10: 1299. 2019-06-06. doi:10.3389/fimmu.2019.01299. PMID 31244845. 
  14. ↑ "A HaemAtlas: characterizing gene expression in differentiated human blood cells". Blood 113 (19): e1-9. May 2009. doi:10.1182/blood-2008-06-162958. PMID 19228925. 
  15. ↑ "Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia". Journal of Leukocyte Biology 106 (3): 581–594. July 2019. doi:10.1002/JLB.MA1118-454R. PMID 31299112. 
  16. ↑ "Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity". The Journal of Biological Chemistry 275 (26): 19594–602. June 2000. doi:10.1074/jbc.M000254200. PMID 10766745. 
  17. ↑ 17.0 17.1 17.2 17.3 "Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes". The EMBO Journal 18 (11): 3090–100. June 1999. doi:10.1093/emboj/18.11.3090. PMID 10357820. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 "A molecular dissection of the repression circuitry of Ikaros". The Journal of Biological Chemistry 277 (31): 27697–705. August 2002. doi:10.1074/jbc.M201694200. PMID 12015313. 
  19. ↑ "Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors". Current Biology 8 (9): 508–15. April 1998. doi:10.1016/s0960-9822(98)70202-7. PMID 9560339. 
  20. ↑ "Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation". The EMBO Journal 16 (8): 2004–13. April 1997. doi:10.1093/emboj/16.8.2004. PMID 9155026. 
  21. ↑ "Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes". Immunity 10 (3): 345–55. March 1999. doi:10.1016/s1074-7613(00)80034-5. PMID 10204490. 
  22. ↑ "Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system". FEBS Letters 447 (1): 76–80. March 1999. doi:10.1016/s0014-5793(99)00265-3. PMID 10218586. 
  23. ↑ "Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities". The Journal of Biological Chemistry 275 (49): 38347–54. December 2000. doi:10.1074/jbc.M005457200. PMID 10978333. 
  24. ↑ "Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression". The Journal of Biological Chemistry 277 (26): 23143–9. June 2002. doi:10.1074/jbc.M202079200. PMID 11959865. 
  25. ↑ "The GATA factor revolution in hematology". Blood 129 (15): 2092–2102. April 2017. doi:10.1182/blood-2016-09-687871. PMID 28179282. 

Further reading

External links



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