KRAB zinc finger proteins

Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are the largest family of transcriptional regulators in higher vertebrates. Characterized by an N-terminal KRAB domain and a C-terminal array of DNA-binding zinc fingers, they participate, together with their co-factor KAP1 (also known as TRIM28), in repression of sequences derived from transposable elements (TEs). Until recently, KRAB-ZFP/KAP1-mediated repression of TEs was thought to lead to irreversible silencing, and the evolutionary selection of KRAB-ZFPs was considered to be just the host component of an arms race against TEs. However, recent advances indicate that KRAB-ZFPs and their TE targets also partner up to establish species-specific regulatory networks. Here, we provide an overview of the KRAB-ZFP gene family, highlighting how its evolutionary history is linked to that of TEs, and how KRAB-ZFPs influence multiple aspects of development and physiology. Summary: This Primer summarises our current understanding of the intriguing family of KRAB-ZFP transcriptional regulators and its contribution to the control, evolution and co-option of transposable elements.

[1]  River Lord High Resolution , 2019, Colorado Review.

[2]  S. Hainsworth,et al.  Critical assessment 26: forensic metallurgy – the difficulties , 2017 .

[3]  D. Trono,et al.  The mouse genome displays highly dynamic populations of KRAB-zinc finger protein genes and related genetic units , 2017, PloS one.

[4]  D. Trono,et al.  KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks , 2017, Nature.

[5]  Andrew Emili,et al.  Multiparameter functional diversity of human C2H2 zinc finger proteins , 2016, Genome research.

[6]  D. Mager,et al.  Endogenous retroviral promoter exaptation in human cancer , 2016, Mobile DNA.

[7]  C. Feschotte,et al.  Regulatory activities of transposable elements: from conflicts to benefits , 2016, Nature Reviews Genetics.

[8]  J. García-Pérez,et al.  The impact of transposable elements on mammalian development , 2016, Development.

[9]  R. Jaenisch,et al.  Molecular Criteria for Defining the Naive Human Pluripotent State , 2016, Cell stem cell.

[10]  A. Churchill,et al.  The Transcriptional Repressive Activity of KRAB Zinc Finger Proteins Does Not Correlate with Their Ability to Recruit TRIM28 , 2016, PloS one.

[11]  M. Lorincz,et al.  Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire. , 2016, Molecular cell.

[12]  Mohammad M. Karimi,et al.  Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma , 2016, Oncogene.

[13]  H. Kazazian,et al.  Roles for retrotransposon insertions in human disease , 2016, Mobile DNA.

[14]  D. Steinemann,et al.  The stem cell zinc finger 1 (SZF1)/ZNF589 protein has a human-specific evolutionary nucleotide DNA change and acts as a regulator of cell viability in the hematopoietic system. , 2016, Experimental hematology.

[15]  Helen M. Rowe,et al.  Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues. , 2016, Developmental cell.

[16]  C. Feschotte,et al.  Regulatory evolution of innate immunity through co-option of endogenous retroviruses , 2016, Science.

[17]  A. Wong,et al.  The evolution of gene expression and binding specificity of the largest transcription factor family in primates , 2016, Evolution; international journal of organic evolution.

[18]  Robert D. Finn,et al.  The Dfam database of repetitive DNA families , 2015, Nucleic Acids Res..

[19]  D. Trono,et al.  The developmental control of transposable elements and the evolution of higher species. , 2015, Annual review of cell and developmental biology.

[20]  D. Greenberg,et al.  Spotting the enemy within: Targeted silencing of foreign DNA in mammalian genomes by the Krüppel-associated box zinc finger protein family , 2015, Mobile DNA.

[21]  D. Greenberg,et al.  Spotting the enemy within: Targeted silencing of foreign DNA in mammalian genomes by the Krüppel-associated box zinc finger protein family , 2015, Mobile DNA.

[22]  D. Chalopin,et al.  Evolutionary impact of transposable elements on genomic diversity and lineage-specific innovation in vertebrates , 2015, Chromosome Research.

[23]  A. Schürmann,et al.  The diabetes gene Zfp69 modulates hepatic insulin sensitivity in mice , 2015, Diabetologia.

[24]  Katherine E. Kyle,et al.  The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes , 2015, Proceedings of the National Academy of Sciences.

[25]  Felix Krueger,et al.  Allele-specific binding of ZFP57 in the epigenetic regulation of imprinted and non-imprinted monoallelic expression , 2015, Genome Biology.

[26]  S. Gasser,et al.  Repeat DNA in genome organization and stability. , 2015, Current opinion in genetics & development.

[27]  Tisha Chung,et al.  A family of transposable elements co-opted into developmental enhancers in the mouse neocortex , 2015, Nature Communications.

[28]  Kyudong Han,et al.  Transposable element-driven transcript diversification and its relevance to genetic disorders. , 2015, Gene.

[29]  E. Füchtbauer,et al.  The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses , 2015, Genes & development.

[30]  Mihai Albu,et al.  C2H2 zinc finger proteins greatly expand the human regulatory lexicon , 2015, Nature Biotechnology.

[31]  Howard Y. Chang,et al.  Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells , 2015, Nature.

[32]  D. Mager,et al.  Mammalian Endogenous Retroviruses. , 2015, Microbiology spectrum.

[33]  H. Ng,et al.  Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells. , 2015, Cell stem cell.

[34]  Floriane Plard,et al.  Comparative Analysis of Transposable Elements Highlights Mobilome Diversity and Evolution in Vertebrates , 2015, Genome biology and evolution.

[35]  D. Trono,et al.  TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells , 2014, Cell reports.

[36]  D. Trono,et al.  As time goes by: KRABs evolve to KAP endogenous retroelements. , 2014, Developmental cell.

[37]  L. Hurst,et al.  Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells , 2014, Nature.

[38]  David Haussler,et al.  An evolutionary arms race between KRAB zinc finger genes 91/93 and SVA/L1 retrotransposons , 2014, Nature.

[39]  Jennifer A. Erwin,et al.  Mobile DNA elements in the generation of diversity and complexity in the brain , 2014, Nature Reviews Neuroscience.

[40]  D. Trono,et al.  Evolutionally dynamic L1 regulation in embryonic stem cells , 2014, Genes & development.

[41]  D. Trono,et al.  Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements , 2014, Genome research.

[42]  A. Sandelin,et al.  Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance , 2014, Nature Genetics.

[43]  F. R. Santoni de Sio Kruppel-associated box (KRAB) proteins in the adaptive immune system , 2014, Nucleus.

[44]  L. Stubbs,et al.  Deep Vertebrate Roots for Mammalian Zinc Finger Transcription Factor Subfamilies , 2014, Genome biology and evolution.

[45]  T. Heidmann,et al.  Paleovirology of ‘syncytins’, retroviral env genes exapted for a role in placentation , 2013, Philosophical Transactions of the Royal Society B: Biological Sciences.

[46]  Ruiqiang Li,et al.  Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells , 2013, Nature Structural &Molecular Biology.

[47]  S. Horvath,et al.  Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing , 2013, Nature.

[48]  A. Lupo,et al.  KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions , 2013, Current genomics.

[49]  Victor V Lobanenkov,et al.  A genome-wide map of CTCF multivalency redefines the CTCF code. , 2013, Cell reports.

[50]  S. Pfaff,et al.  Transposable elements as genetic regulatory substrates in early development. , 2013, Trends in cell biology.

[51]  Ray Marcel Marin-Florez,et al.  A KRAB/KAP1-miRNA Cascade Regulates Erythropoiesis Through Stage-Specific Control of Mitophagy , 2013, Science.

[52]  Helen M. Rowe,et al.  TRIM28 repression of retrotransposon-based enhancers is necessary to preserve transcriptional dynamics in embryonic stem cells , 2013, Genome research.

[53]  Andrea Corsinotti,et al.  Global and Stage Specific Patterns of Krüppel-Associated-Box Zinc Finger Protein Gene Expression in Murine Early Embryonic Cells , 2013, PloS one.

[54]  J. Baker,et al.  Endogenous retroviruses function as species-specific enhancer elements in the placenta , 2013, Nature Genetics.

[55]  Helen M. Rowe,et al.  De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET , 2013, Development.

[56]  D. Mager,et al.  Transposable elements: an abundant and natural source of regulatory sequences for host genes. , 2012, Annual review of genetics.

[57]  James H. Thomas,et al.  KAP1 regulates gene networks controlling T‐cell development and responsiveness , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  D. Trono,et al.  The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development. , 2012, Cell reports.

[59]  D. Trono,et al.  Liver‐specific ablation of Krüppel‐associated box–associated protein 1 in mice leads to male‐predominant hepatosteatosis and development of liver adenoma , 2012, Hepatology.

[60]  T. Shimogori,et al.  A SINE-Derived Element Constitutes a Unique Modular Enhancer for Mammalian Diencephalic Fgf8 , 2012, PloS one.

[61]  D. C. Schultz,et al.  The KRAB Zinc Finger Protein RSL1 Regulates Sex- and Tissue-Specific Promoter Methylation and Dynamic Hormone-Responsive Chromatin Configuration , 2012, Molecular and Cellular Biology.

[62]  D. C. Hancks,et al.  Active human retrotransposons: variation and disease. , 2012, Current opinion in genetics & development.

[63]  D. Mager,et al.  C-GATE - catalogue of genes affected by transposable elements , 2012, Mobile DNA.

[64]  James H. Thomas,et al.  KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function. , 2012, Blood.

[65]  J. Nichols,et al.  The Stat6-regulated KRAB domain zinc finger protein Zfp157 regulates the balance of lineages in mammary glands and compensates for loss of Gata-3. , 2012, Genes & development.

[66]  T. Honjo,et al.  TRIM28 prevents autoinflammatory T cell development in vivo , 2012, Nature Immunology.

[67]  Yan Zeng,et al.  Knockdown of ZNF268, which Is Transcriptionally Downregulated by GATA-1, Promotes Proliferation of K562 Cells , 2012, PloS one.

[68]  K. Liem,et al.  TRIM28 is required by the mouse KRAB domain protein ZFP568 to control convergent extension and morphogenesis of extra-embryonic tissues , 2011, Development.

[69]  M. Kyba,et al.  Zinc Finger Protein ZFP57 Requires Its Co-factor to Recruit DNA Methyltransferases and Maintains DNA Methylation Imprint in Embryonic Stem Cells via Its Transcriptional Repression Domain* , 2011, The Journal of Biological Chemistry.

[70]  M. Batzer,et al.  Repetitive Elements May Comprise Over Two-Thirds of the Human Genome , 2011, PLoS genetics.

[71]  D. Trono,et al.  In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions , 2011, Molecular cell.

[72]  R. Löwer,et al.  The non-autonomous retrotransposon SVA is trans-mobilized by the human LINE-1 protein machinery , 2011, Nucleic acids research.

[73]  James H. Thomas,et al.  Coevolution of retroelements and tandem zinc finger genes. , 2011, Genome research.

[74]  T. Heidmann,et al.  A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast , 2011, Proceedings of the National Academy of Sciences.

[75]  Peggy J. Farnham,et al.  KAP1 Protein: An Enigmatic Master Regulator of the Genome* , 2011, The Journal of Biological Chemistry.

[76]  Ying Zhang,et al.  Distributions of Transposable Elements Reveal Hazardous Zones in Mammalian Introns , 2011, PLoS Comput. Biol..

[77]  A. Lupo,et al.  ZNF224: Structure and role of a multifunctional KRAB-ZFP protein. , 2011, The international journal of biochemistry & cell biology.

[78]  Maho Shibata,et al.  The mouse KRAB zinc-finger protein CHATO is required in embryonic-derived tissues to control yolk sac and placenta morphogenesis. , 2011, Developmental biology.

[79]  Henriette O'Geen,et al.  ZNF274 Recruits the Histone Methyltransferase SETDB1 to the 3′ Ends of ZNF Genes , 2010, PloS one.

[80]  Huanjie Shao,et al.  PU.1 can regulate the ZNF300 promoter in APL-derived promyelocytes HL-60. , 2010, Leukemia research.

[81]  G. Mizuguchi,et al.  Stepwise Histone Replacement by SWR1 Requires Dual Activation with Histone H2A.Z and Canonical Nucleosome , 2010, Cell.

[82]  S. Izui,et al.  Role of endogenous retroviruses in murine SLE. , 2010, Autoimmunity reviews.

[83]  Katja Nowick,et al.  Rapid sequence and expression divergence suggest selection for novel function in primate-specific KRAB-ZNF genes. , 2010, Molecular biology and evolution.

[84]  G. Montano,et al.  Biochemical and functional interaction between ZNF224 and ZNF255, two members of the Kruppel-like zinc-finger protein family and WT1 protein isoforms. , 2010, Human molecular genetics.

[85]  Christopher Power,et al.  Human endogenous retroviruses and multiple sclerosis: Innocent bystanders or disease determinants? , 2010, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.

[86]  D. Mager,et al.  Potential mechanisms of endogenous retroviral-mediated genomic instability in human cancer. , 2010, Seminars in cancer biology.

[87]  H. Kazazian,et al.  SVA retrotransposons: Evolution and genetic instability. , 2010, Seminars in cancer biology.

[88]  G. Bourque,et al.  Transposable elements have rewired the core regulatory network of human embryonic stem cells , 2010, Nature Genetics.

[89]  Ralph Stadhouders,et al.  Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma , 2010, Nature Medicine.

[90]  P. Deininger,et al.  Somatic expression of LINE-1 elements in human tissues , 2010, Nucleic acids research.

[91]  H. Kimura,et al.  Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET , 2010, Nature.

[92]  Helen M. Rowe,et al.  KAP1 controls endogenous retroviruses in embryonic stem cells , 2010, Nature.

[93]  L. Stubbs,et al.  Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain , 2009, Proceedings of the National Academy of Sciences.

[94]  D. Mager,et al.  Endogenous retroviral LTRs as promoters for human genes: a critical assessment. , 2009, Gene.

[95]  Victor X. Jin,et al.  Genomic Targets of the KRAB and SCAN Domain-containing Zinc Finger Protein 263* , 2009, The Journal of Biological Chemistry.

[96]  T. Nagase,et al.  KAP1-independent transcriptional repression of SCAN-KRAB-containing zinc finger proteins. , 2009, Biochemical and biophysical research communications.

[97]  G. Agrimi,et al.  Transcription of the mitochondrial citrate carrier gene: identification of a silencer and its binding protein ZNF224. , 2009, Biochemical and biophysical research communications.

[98]  P. Opolon,et al.  Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene , 2009, Proceedings of the National Academy of Sciences.

[99]  J. Kawai,et al.  The regulated retrotransposon transcriptome of mammalian cells , 2009, Nature Genetics.

[100]  S. Goff,et al.  Embryonic stem cells use ZFP809 to silence retroviral DNAs , 2009, Nature.

[101]  R. Emerson,et al.  Adaptive Evolution in Zinc Finger Transcription Factors , 2009, PLoS genetics.

[102]  C. Sandi,et al.  KAP1-Mediated Epigenetic Repression in the Forebrain Modulates Behavioral Vulnerability to Stress , 2008, Neuron.

[103]  E. Liu,et al.  Evolution of the mammalian transcription factor binding repertoire via transposable elements. , 2008, Genome research.

[104]  I. Maksakova,et al.  Endogenous retroviruses , 2008, Cellular and Molecular Life Sciences.

[105]  P. Leder,et al.  A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. , 2008, Developmental cell.

[106]  C. Feschotte,et al.  DNA transposons and the evolution of eukaryotic genomes. , 2007, Annual review of genetics.

[107]  M. Wiznerowicz,et al.  The Krüppel-associated Box Repressor Domain Can Trigger de Novo Promoter Methylation during Mouse Early Embryogenesis* , 2007, Journal of Biological Chemistry.

[108]  D. Haussler,et al.  Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53 , 2007, Proceedings of the National Academy of Sciences.

[109]  S. Goff,et al.  TRIM28 Mediates Primer Binding Site-Targeted Silencing of Murine Leukemia Virus in Embryonic Cells , 2007, Cell.

[110]  C. Feschotte,et al.  The evolutionary history of human DNA transposons: evidence for intense activity in the primate lineage. , 2007, Genome research.

[111]  M. Pagel,et al.  Origin of avian genome size and structure in non-avian dinosaurs , 2007, Nature.

[112]  D. C. Schultz,et al.  The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression , 2006, Molecular and Cellular Biology.

[113]  Liane Gagnier,et al.  Retroviral Elements and Their Hosts: Insertional Mutagenesis in the Mouse Germ Line , 2006, PLoS genetics.

[114]  S. d'Auria,et al.  Structure/function of KRAB repression domains: Structural properties of KRAB modules inferred from hydrodynamic, circular dichroism, and FTIR spectroscopic analyses , 2005, Proteins.

[115]  A. Lupo,et al.  The Krüppel-like zinc-finger protein ZNF224 represses aldolase A gene transcription by interacting with the KAP-1 co-repressor protein. , 2005, Gene.

[116]  Elaine R. Mardis,et al.  A physical map of the chicken genome , 2004, Nature.

[117]  A. Evsikov,et al.  Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. , 2004, Developmental cell.

[118]  H. Kazazian Mobile Elements: Drivers of Genome Evolution , 2004, Science.

[119]  Raymond D. Miller,et al.  Regulator of sex-limitation (Rsl) encodes a pair of KRAB zinc-finger genes that control sexually dimorphic liver gene expression. , 2003, Genes & Development.

[120]  R. Urrutia KRAB-containing zinc-finger repressor proteins , 2003, Genome Biology.

[121]  L. N. van de Lagemaat,et al.  Retroelement distributions in the human genome: variations associated with age and proximity to genes. , 2002, Genome research.

[122]  G. Maul,et al.  SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. , 2002, Genes & development.

[123]  W A Scaringe,et al.  Frequency of recent retrotransposition events in the human factor IX gene , 2001, Human mutation.

[124]  A. Jheon,et al.  Characterization of a Novel KRAB/C2H2Zinc Finger Transcription Factor Involved in Bone Development* , 2001, The Journal of Biological Chemistry.

[125]  S. Iuchi,et al.  Three classes of C2H2 zinc finger proteins , 2001, Cellular and Molecular Life Sciences CMLS.

[126]  C. Schumacher,et al.  Identification of SCAN dimerization domains in four gene families. , 2001, Biochimica et biophysica acta.

[127]  J. Friedman,et al.  Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2alpha subunit of NuRD. , 2001, Genes & development.

[128]  J. Mccoy,et al.  Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis , 2000, Nature.

[129]  R. Losson,et al.  Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family , 1999, The EMBO journal.

[130]  R. Deberardinis,et al.  Rapid amplification of a retrotransposon subfamily is evolving the mouse genome , 1998, Nature Genetics.

[131]  C. Walsh,et al.  Transcription of IAP endogenous retroviruses is constrained by cytosine methylation , 1998, Nature Genetics.

[132]  C. Pabo,et al.  High-resolution structures of variant Zif268-DNA complexes: implications for understanding zinc finger-DNA recognition. , 1998, Structure.

[133]  D. Speicher,et al.  KAP-1, a novel corepressor for the highly conserved KRAB repression domain. , 1996, Genes & development.

[134]  L. Samuelson,et al.  Amylase gene structures in primates: retroposon insertions and promoter evolution. , 1996, Molecular biology and evolution.

[135]  B. Grondin,et al.  The KRAB Zinc Finger Gene ZNF74 Encodes an RNA-binding Protein Tightly Associated with the Nuclear Matrix* , 1996, The Journal of Biological Chemistry.

[136]  Yusuke Nakamura,et al.  Mutation analysis in the BRCA2 gene in primary breast cancers , 1996, Nature Genetics.

[137]  J. Bonventre,et al.  The Krüppel-associated box-A (KRAB-A) domain of zinc finger proteins mediates transcriptional repression. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[138]  M. Meisler,et al.  Endogenous retroviral sequences are required for tissue-specific expression of a human salivary amylase gene. , 1992, Genes & development.

[139]  J. Martial,et al.  The evolutionarily conserved Krüppel-associated box domain defines a subfamily of eukaryotic multifingered proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[140]  J. Stavenhagen,et al.  An ancient provirus has imposed androgen regulation on the adjacent mouse sex-limited protein gene , 1988, Cell.

[141]  S. Antonarakis,et al.  Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man , 1988, Nature.

[142]  W. Doolittle,et al.  Selfish genes, the phenotype paradigm and genome evolution , 1980, Nature.

[143]  R. Britten,et al.  Gene regulation for higher cells: a theory. , 1969, Science.

[144]  B. Mcclintock The origin and behavior of mutable loci in maize , 1950, Proceedings of the National Academy of Sciences.

[145]  D. Stoppa-Lyonnet,et al.  An Alu-mediated 6-kb duplication in the BRCA1 gene: a new founder mutation? , 1999, American journal of human genetics.

[146]  John M. Coffin,et al.  Retroviral Pathogenesis -- Retroviruses , 1997 .