Evolution of C2H2 Zinc‐finger Gene Families in Mammals

Abstract

The C2H2 zinc‐finger encode the largest class of transcription factors and second largest gene family in the human genome. Based on the presence or absence of an N‐terminal effector domain, they are grouped into different subfamilies. The KRAB (Kruppel‐associated box) C2H2‐ZNF subfamily, found specifically in tetrapods, constitutes about half of these genes in human and mouse. Often found in clusters, the C2H2‐ZNF genes have evolved independently in various species at the level of genes, effector motifs and the zinc‐finger region. More specifically, in recent times there has been an unprecedented expansion of these genes in mammalian genomes. Cross‐species comparisons reveal a series of dynamic duplications and gene loss events that led to rapid and lineage‐specific evolution of these genes in different vertebrate genomes. Both lineage‐specific variation in the number, sequence and subfamilies of C2H2‐ZNF genes and differential expansion in genomes may be determinant for functions related to speciation.

Key Concepts:

  • C2H2‐ZNF genes are ubiquitously present in all organisms ranging from bacteria to human and are often arranged in a clustered organisation.

  • A massive expansion in the number of C2H2‐ZNF genes occurred from yeast to primates.

  • Besides gene duplication, loss and to a certain extent pseudogenisation are contributing factors in the evolution of the C2H2‐ZNF gene family.

  • C2H2‐ZNF genes follow the ‘Birth and Death’ model of evolution contributing to differential and independent evolution of the C2H2‐ZNF genes in different genomes.

  • C2H2‐ZNF genes encode DNA‐ and RNA‐binding proteins presumably involved in gene expression as transcription factors or possibly RNA regulators.

  • Members of the C2H2‐ZNF family are characterised by tandemly repeated zinc‐finger motifs involved in nucleic acid binding and are grouped into different subfamilies based on their N‐terminal regulatory domains which include SCAN, KRAB, BTB, HOMEO and SET domains.

  • Because of their tandemly repeated zinc‐finger motifs, members of the C2H2‐ZNF family are named multifingered C2H2‐ZNF genes. These motifs are prone to be duplicated, lost or to degenerate during evolution.

  • The KRAB and SCAN domains are solely confined to vertebrates. In all vertebrates, the KRAB domain is found within C2H2‐ZNF proteins.

  • The KRAB domain‐encoding C2H2‐ZNF genes define the largest and a rapidly evolving C2H2‐ZNF subfamily in vertebrates and particularly in mammals.

  • The study of the evolution of the C2H2‐ZNF genes in various genomes may help to elucidate their possible role in functions associated with speciation.

Keywords: C2H2 zinc‐finger genes; evolution; mammals; duplication; KRAB; SCAN

Figure 1.

The different C2H2‐ZNF subfamilies. (a) The three‐dimensional structure of the C2H2‐ZNF protein is shown. The two cysteine residues on the β strand in green can be seen interacting with the two histidine residues in orange on the α helix. The interacting zinc ion is shown in red in the centre. (b) The different effector domains found associated with the C2H2‐ZNF proteins are shown. These proteins comprise of three regions: The N‐terminal effector domain, the Spacer region and the C‐terminal zinc‐finger region. The blue circles represent the individual zinc‐finger domains of the zinc‐finger region. As schematised, SCAN and KRAB C2H2‐ZNF proteins contain a higher number of zinc‐finger domains than the BTB, SET and HOMEO C2H2‐ZNF. The consensus sequences of the KRAB (A, B, b and C), SCAN, BTB, SET and HOMEO domains are also shown.

Figure 2.

Distribution of the C2H2‐ZNF genes in different genomes. The total number of C2H2‐ZNF genes in different genomes is shown. There has been a massive expansion in the number of C2H2‐ZNF genes over the course of evolution. Humans (Homo sapiens) (Tadepally et al., ; Ding et al., ) have the highest number of genes as compared to the other species like Mouse (Mus musculus) (Ding et al., ), Chicken (Gallus gallus) (Thomas and Emerson, ), Fly (Drosophila melanogaster), Worm (Caenorhabditis elegans), Yeast (Saccharomyces cerevisiae) and Plant (Arabidopsis thaliana) (Looman et al., ).

Figure 3.

Distribution of the various effector domains associated with C2H2‐ZNF proteins in various species over the course of evolution. The presence or absence of the various effector domains associated at the N‐terminal of the zinc‐finger region from C2H2‐ZNF proteins in various species is shown here. C2H2‐ZNF proteins are found throughout evolution in prokaryotes (bacteria) and eukaryotes (including metazoan and nonmetazoan such as plant). As illustrated, while the BTB domain is found in all species except bacteria, the SCAN and KRAB domains are found in vertebrates. The KRAB domain is more specifically confined to tetrapods. Chicken lost the SCAN domain during evolution. * indicates that in lower vertebrates like frog and fish, the SCAN domain is present but is not associated with C2H2‐ZNF proteins. The blue circles represent the individual zinc‐finger domains of the zinc‐finger region.

Figure 4.

Distribution of the C2H2‐ZNF genes in the different subfamilies from the human genome. (a) The distribution of human C2H2‐ZNF genes in the different subfamilies defined by the effector motifs is shown. The KRAB C2H2‐ZNF subfamily constitutes nearly half of all the C2H2‐ZNF genes in human. None represents the C2H2‐ZNF genes not associated with any typical effector motif. (b) The distribution of C2H2‐ZNF genes from the different subfamilies that are present in clusters is shown here. Almost 90% of the KRAB and SCAN motif‐containing C2H2‐ZNF genes are present in clusters as opposed to the genes associated with the other effector motifs which have a higher tendency to be present as singletons.

close

References

Banerjee‐Basu S, Ferlanti ES, Ryan JF and Baxevanis AD (1999) The Homeodomain Resource: sequences, structures and genomic information. Nucleic Acids Research 27: 336–337.

Bellefroid EJ, Poncelet DA, Lecocq PJ, Revelant O and Martial JA (1991) The evolutionarily conserved Kruppel‐associated box domain defines a subfamily of eukaryotic multifingered proteins. Proceedings of the National Academy of Sciences of the USA 88: 3608–3612.

Birtle Z and Ponting CP (2006) Meisetz and the birth of the KRAB motif. Bioinformatics 22: 2841–2845.

Bouhouche N, Syvanen M and Kado CI (2000) The origin of prokaryotic C2H2 zinc finger regulators. Trends in Microbiology 8: 77–81.

Collins T, Stone JR and Williams AJ (2001) All in the family: the BTB/POZ, KRAB, and SCAN domains. Molecular and Cellular Biology 21: 3609–3615.

David G, Alland L, Hong SH et al. (1998) Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia‐associated PLZF protein. Oncogene 16: 2549–2556.

Dehal P, Predki P, Olsen AS et al. (2001) Human chromosome 19 and related regions in mouse: conservative and lineage‐specific evolution. Science 293: 104–111.

Dettman EJ and Justice MJ (2008) The zinc finger SET domain gene Prdm14 is overexpressed in lymphoblastic lymphomas with retroviral insertions at Evi32. PLoS One 3: e3823.

Ding G, Lorenz P, Kreutzer M, Li Y and Thiesen HJ (2009) SysZNF: the C2H2 zinc finger gene database. Nucleic Acids Research 37: D267–D273.

Edelstein LC and Collins T (2005) The SCAN domain family of zinc finger transcription factors. Gene 359: 1–17.

Eichler EE, Hoffman SM, Adamson AA et al. (1998) Complex beta‐satellite repeat structures and the expansion of the zinc finger gene cluster in 19p12. Genome Research 8: 791–808.

Emerson RO and Thomas JH (2009) Adaptive evolution in zinc finger transcription factors. PLoS Genetics 5: e1000325.

Germain‐Desprez D, Bazinet M, Bouvier M and Aubry M (2003) Oligomerization of transcriptional intermediary factor 1 regulators and interaction with ZNF74 nuclear matrix protein revealed by bioluminescence resonance energy transfer in living cells. Journal of Biological Chemistry 278: 22367–22373.

Gilad Y, Man O and Glusman G (2005) A comparison of the human and chimpanzee olfactory receptor gene repertoires. Genome Research 15: 224–230.

Grondin B, Bazinet M and Aubry M (1996) The KRAB zinc finger gene ZNF74 encodes an RNA‐binding protein tightly associated with the nuclear matrix. Journal of Biological Chemistry 271: 15458–15467.

Hamilton AT, Huntley S, Tran‐Gyamfi M et al. (2006) Evolutionary expansion and divergence in the ZNF91 subfamily of primate‐specific zinc finger genes. Genome Research 16: 584–594.

Hillier LW, Miller W and Birney E (2004) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432: 695–716.

Huntley S, Baggott DM, Hamilton AT et al. (2006) A comprehensive catalog of human KRAB‐associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors. Genome Research 16: 669–677.

Klug A and Schwabe JW (1995) Protein motifs 5. Zinc fingers. FASEB Journal 9: 597–604.

Krebs CJ, Larkins LK, Price R et al. (2003) Regulator of sex‐limitation (Rsl) encodes a pair of KRAB zinc‐finger genes that control sexually dimorphic liver gene expression. Genes & Development 17: 2664–2674.

Lee MS, Gippert GP, Soman KV, Case DA and Wright PE (1989) Three‐dimensional solution structure of a single zinc finger DNA‐binding domain. Science 245: 635–637.

Li J, Chen X, Gong X et al. (2009) A transcript profiling approach reveals the zinc finger transcription factor ZNF191 is a pleiotropic factor. BMC Genomics 10: 241.

Li J, Chen X, Yang H et al. (2006) The zinc finger transcription factor 191 is required for early embryonic development and cell proliferation. Experimental Cell Research 312: 3990–3998.

Looman C, Abrink M, Mark C and Hellman L (2002) KRAB zinc finger proteins: an analysis of the molecular mechanisms governing their increase in numbers and complexity during evolution. Molecular Biology and Evolution 19: 2118–2130.

Looman C, Hellman L and Abrink M (2004) A novel Kruppel‐associated box identified in a panel of mammalian zinc finger proteins. Mammalian Genome 15: 35–40.

Mascle XH, Germain‐Desprez D, Huynh P, Estephan P and Aubry M (2007) Sumoylation of the transcriptional intermediary factor 1beta (TIF1beta), the co‐repressor of the KRAB multifinger proteins, is required for its transcriptional activity and is modulated by the KRAB domain. Journal of Biological Chemistry 282: 10190–10202.

Nei M, Gu X and Sitnikova T (1997) Evolution by the birth‐and‐death process in multigene families of the vertebrate immune system. Proceedings of the National Academy of Sciences of the USA 94: 7799–7806.

Niimura Y and Nei M (2003) Evolution of olfactory receptor genes in the human genome. Proceedings of the National Academy of Sciences of the USA 100: 12235–12240.

Niimura Y and Nei M (2007) Extensive gains and losses of olfactory receptor genes in mammalian evolution. PLoS One 2: e708.

Ohta T (2000) Evolution of gene families. Gene 259: 45–52.

Peterson FC, Hayes PL, Waltner JK et al. (2006) Structure of the SCAN domain from the tumor suppressor protein MZF1. Journal of Molecular Biology 363: 137–147.

Quignon P, Kirkness E, Cadieu E et al. (2003) Comparison of the canine and human olfactory receptor gene repertoires. Genome Biology 4: R80.

Ravassard P, Cote F, Grondin B et al. (1999) ZNF74, a gene deleted in DiGeorge syndrome, is expressed in human neural crest‐derived tissues and foregut endoderm epithelia. Genomics 62: 82–85.

Rhodes D and Klug A (1993) Zinc fingers. Scientific American 268: 56–59, 62–55.

Ryan RF, Schultz DC, Ayyanathan K et al. (1999) KAP‐1 corepressor protein interacts and colocalizes with heterochromatic and euchromatic HP1 proteins: a potential role for Kruppel‐associated box‐zinc finger proteins in heterochromatin‐mediated gene silencing. Molecular and Cellular Biology 19: 4366–4378.

Sander TL, Haas AL, Peterson MJ and Morris JF (2000) Identification of a novel SCAN box‐related protein that interacts with MZF1B. The leucine‐rich SCAN box mediates hetero‐ and homoprotein associations. Journal of Biological Chemistry 275: 12857–12867.

Sander TL, Stringer KF, Maki JL et al. (2003) The SCAN domain defines a large family of zinc finger transcription factors. Gene 310: 29–38.

Schmidt D and Durrett R (2004) Adaptive evolution drives the diversification of zinc‐finger binding domains. Molecular Biology and Evolution 21: 2326–2339.

Schuh R, Aicher W, Gaul U et al. (1986) A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Kruppel, a Drosophila segmentation gene. Cell 47: 1025–1032.

Shannon M, Hamilton AT, Gordon L, Branscomb E and Stubbs L (2003) Differential expansion of zinc‐finger transcription factor loci in homologous human and mouse gene clusters. Genome Research 13: 1097–1110.

Sharon D, Glusman G, Pilpel Y et al. (1999) Primate evolution of an olfactory receptor cluster: diversification by gene conversion and recent emergence of pseudogenes. Genomics 61: 24–36.

Sitnikova T and Nei M (1998) Evolution of immunoglobulin kappa chain variable region genes in vertebrates. Molecular Biology and Evolution 15: 50–60.

Stogios PJ, Downs GS, Jauhal JJ, Nandra SK and Prive GG (2005) Sequence and structural analysis of BTB domain proteins. Genome Biology 6: R82.

Stone JR, Maki JL, Blacklow SC and Collins T (2002) The SCAN domain of ZNF174 is a dimer. Journal of Biological Chemistry 277: 5448–5452.

Tadepally HD, Burger G and Aubry M (2008) Evolution of C2H2‐zinc finger genes and subfamilies in mammals: species‐specific duplication and loss of clusters, genes and effector domains. BMC Evolution Biology 8: 176.

Tanaka K, Matsumoto Y, Nakatani F, Iwamoto Y and Yamada Y (2000) A zinc finger transcription factor, alphaA‐crystallin binding protein 1, is a negative regulator of the chondrocyte‐specific enhancer of the alpha1(II) collagen gene. Molecular and Cellular Biology 20: 4428–4435.

Theunissen O, Rudt F, Guddat U, Mentzel H and Pieler T (1992) RNA and DNA binding zinc fingers in Xenopus TFIIIA. Cell 71: 679–690.

Thomas JH and Emerson RO (2009) Evolution of C2H2‐zinc finger genes revisited. BMC Evolution Biology 9: 51.

Urrutia R (2003) KRAB‐containing zinc‐finger repressor proteins. Genome Biology 4: 231.

Venter JC, Adams MD, Myers EW et al. (2001) The sequence of the human genome. Science 291: 1304–1351.

Wong CW and Privalsky ML (1998) Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF‐RARalpha, and BCL‐6. Journal of Biological Chemistry 273: 27695–27702.

Zheng L, Pan H, Li S et al. (2000) Sequence‐specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Molecular Cell 6: 757–768.

Further Reading

Hirasawa R and Feil R (2008) A KRAB domain zinc finger protein in imprinting and disease. Developmental Cell 15(4): 487–488.

Howng SY, Avila RL, Emery B et al. (2010) ZFP191 is required by oligodendrocytes for CNS myelination. Genes & Development 24(3): 301–311.

Itokawa Y, Yanagawa T, Yamakawa H et al. (2009) KAP1‐independent transcriptional repression of SCAN‐KRAB‐containing zinc finger proteins. Biochemistry and Biophysics Research Communication 388(4): 689–694.

Krebs CJ and Robins DM (2009) A pair of mouse KRAB zinc finger proteins modulates multiple indicators of female reproduction. Biological Reproduction. doi: 10.1095/biolreprod.109.080846 [published ahead of print December 30, 2009].

Nowick K and Stubbs L (2010) Lineage‐specific transcription factors and the evolution of gene regulatory networks. Brief Function of Genomic and Proteomic 9(1): 65–78.

Shannon M, Kim J, Ashworth L et al. (1998) Tandem zinc‐finger gene families in mammals: insights and unanswered questions. DNA Sequence 8(5): 303–315.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Dhwani Tadepally, Hamsa, and Aubry, Muriel(May 2010) Evolution of C2H2 Zinc‐finger Gene Families in Mammals. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021738]