Promoter microsatellites as modulators of human gene expression.

Microsatellites in and around genes have been shown to modulate levels of gene expression in multiple organisms, ranging from bacteria to humans. Here we will discuss promoter microsatellites known to modulate gene expression, with a few key examples related to the human brain. Many of the microsatellites we discuss are highly conserved in mammals, indicating that selection may favor their retention as "tuning knobs" of gene expression. We will also discuss the mechanisms by which microsatellites in promoters can alter gene expression as they expand and contract, with particular attention to secondary structures like Z-DNA and H-DNA. We suggest that promoter microsatellites, especially those that are highly conserved, may be an important source of human phenotypic variation.

[1]  Liqing Zhang,et al.  Housekeeping and tissue-specific genes differ in simple sequence repeats in the 5'-UTR region. , 2008, Gene.

[2]  B. Plunkett,et al.  Variation in dinucleotide (GT) repeat sequence in the first exon of the STAT6 gene is associated with atopic asthma and differentially regulates the promoter activity in vitro , 2004, Journal of Medical Genetics.

[3]  J. Mallet,et al.  Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsatellite. , 2001, Human molecular genetics.

[4]  Marika Paaver,et al.  A functional NOS1 promoter polymorphism interacts with adverse environment on functional and dysfunctional impulsivity , 2011, Psychopharmacology.

[5]  G. Koren,et al.  Purification and preliminary characterization of a cardiac Kv1.5 repressor element binding factor. , 1999, Circulation research.

[6]  S. Snyder,et al.  Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase , 1995, Nature.

[7]  Alexander Rich,et al.  Characterization of Z-DNA as a nucleosome-boundary element in yeast Saccharomyces cerevisiae , 2007, Proceedings of the National Academy of Sciences.

[8]  H. Orzechowski,et al.  Regulation of the major isoform of human endothelin-converting enzyme-1 by a strong housekeeping promoter modulated by polymorphic microsatellites , 2003, Journal of hypertension.

[9]  Y. Kohwi,et al.  Altered gene expression correlates with DNA structure. , 1991, Genes & development.

[10]  Miriam K. Konkel,et al.  Genome analysis of the platypus reveals unique signatures of evolution , 2008, Nature.

[11]  J. Shklover,et al.  Quadruplex structures of muscle gene promoter sequences enhance in vivo MyoD-dependent gene expression , 2010, Nucleic acids research.

[12]  S. Wölfl,et al.  Transcription of the human corticotropin-releasing hormone gene in NPLC cells is correlated with Z-DNA formation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  D. Hood,et al.  Microsatellite instability regulates transcription factor binding and gene expression. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Gruss,et al.  Pax6 Modulates the Dorsoventral Patterning of the Mammalian Telencephalon , 2000, The Journal of Neuroscience.

[15]  Hiromitsu Shimizu,et al.  A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. , 2003, Pharmacogenetics.

[16]  Richard Moxon,et al.  Bacterial contingency loci: the role of simple sequence DNA repeats in bacterial adaptation. , 2006, Annual review of genetics.

[17]  Judith Roth,et al.  A polymorphic microsatellite that mediates induction of PIG3 by p53 , 2002, Nature Genetics.

[18]  J. Shelhamer,et al.  Characterization of the promoter for the human 85 kDa cytosolic phospholipase A2 gene. , 1994, Nucleic acids research.

[19]  E. Rassart,et al.  Triplex-forming oligonucleotides with unexpected affinity for a nontargeted GA repeat sequence. , 1997, Antisense & nucleic acid drug development.

[20]  B. Johnston,et al.  The S1-sensitive form of d(C-T)n.d(A-G)n: chemical evidence for a three-stranded structure in plasmids. , 1988, Science.

[21]  B. Lell,et al.  DNA phasing by TA dinucleotide microsatellite length determines in vitro and in vivo expression of the gp91phox subunit of NADPH oxidase and mediates protection against severe malaria. , 2004, The Journal of infectious diseases.

[22]  S. Wölfl,et al.  Transcription of human c‐myc in permeabilized nuclei is associated with formation of Z‐DNA in three discrete regions of the gene. , 1992, The EMBO journal.

[23]  B. Pakkenberg,et al.  Spatiotemporal Distribution of PAX6 and MEIS2 Expression and Total Cell Numbers in the Ganglionic Eminence in the Early Developing Human Forebrain , 2010, Developmental Neuroscience.

[24]  A. Meyer-Lindenberg,et al.  Genetic variants in AVPR1A linked to autism predict amygdala activation and personality traits in healthy humans , 2009, Molecular Psychiatry.

[25]  M. Achtman,et al.  Variable expression of the Opc outer membrane protein in Neisseria meningitidis is caused by size variation of a promoter containing poly‐cytidine , 1994, Molecular microbiology.

[26]  C. Panhuysen,et al.  Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele , 2009, Human Genetics.

[27]  C. Nguyen,et al.  Benzoquinoquinoxaline derivatives stabilize and cleave H-DNA and repress transcription downstream of a triplex-forming sequence. , 2005, Journal of molecular biology.

[28]  K. Kim,et al.  Roles of CCAAT/enhancer-binding protein and its binding site on repression and derepression of acetyl-CoA carboxylase gene. , 1994, The Journal of biological chemistry.

[29]  C. Pang,et al.  AC and AG dinucleotide repeats in the PAX6 P1 promoter are associated with high myopia , 2009, Molecular vision.

[30]  Ann-Christine Ehlis,et al.  Influence of functional variant of neuronal nitric oxide synthase on impulsive behaviors in humans. , 2009, Archives of general psychiatry.

[31]  J. Kurth,et al.  The effect of a promoter polymorphism on the transcription of nitric oxide synthase 1 and its relevance to Parkinson's disease , 2009, Journal of neuroscience research.

[32]  K. Lesch,et al.  The effect of a functional NOS1 promoter polymorphism on impulsivity is moderated by platelet MAO activity , 2010, Psychopharmacology.

[33]  Laurence H. Hurley,et al.  Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions. , 2008, Biochimie.

[34]  O. Griffith,et al.  Mammalian nitric oxide synthases. , 1999, Advances in enzymology and related areas of molecular biology.

[35]  G. Gilkeson,et al.  A GA microsatellite in the Fli1 promoter modulates gene expression and is associated with systemic lupus erythematosus patients without nephritis , 2010, Arthritis research & therapy.

[36]  S. Brahmachari,et al.  Poly purine.pyrimidine sequences upstream of the beta-galactosidase gene affect gene expression in Saccharomyces cerevisiae , 2001, BMC Molecular Biology.

[37]  G. Gilkeson,et al.  Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes. , 2008, Molecular immunology.

[38]  F. Moreau,et al.  Mutational analysis of the promoter region of the porA gene of Neisseria meningitidis. , 1999, Gene.

[39]  F. Koch-Nolte,et al.  DNA methylation and Z‐DNA formation as mediators of quantitative differences in the expression of alleles , 2001, Immunological reviews.

[40]  S. Yip,et al.  PAX6 Haplotypes Are Associated with High Myopia in Han Chinese , 2011, PloS one.

[41]  V. Iyer,et al.  Poly(dA:dT), a ubiquitous promoter element that stimulates transcription via its intrinsic DNA structure. , 1995, The EMBO journal.

[42]  Nancy L Pedersen,et al.  Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans , 2008, Proceedings of the National Academy of Sciences.

[43]  Michael V. Bland,et al.  Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity , 2008, Pharmacogenetics and genomics.

[44]  T. Krieg,et al.  A purine-rich sequence in the human BM-40 gene promoter region is a prerequisite for maximum transcription. , 1995, Matrix biology : journal of the International Society for Matrix Biology.

[45]  Guliang Wang,et al.  Z-DNA, an active element in the genome. , 2007, Frontiers in bioscience : a journal and virtual library.

[46]  D. Davidson,et al.  The role of Pax-6 in eye and nasal development. , 1995, Development.

[47]  Randy Z. Wu,et al.  Positioned and G/C-capped poly(dA:dT) tracts associate with the centers of nucleosome-free regions in yeast promoters. , 2010, Genome research.

[48]  J. Strobl,et al.  Z-DNA formation in the rat growth hormone gene promoter region , 1990, Molecular and cellular biology.

[49]  J. Dixon,et al.  Z-DNA in the rat somatostatin gene. , 1985, The Journal of biological chemistry.

[50]  Anthony J. Hannan Tandem repeat polymorphisms : genetic plasticity, neural diversity and disease , 2012 .

[51]  S. Shibahara,et al.  Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. , 2000, American journal of human genetics.

[52]  R. Memmott,et al.  A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity , 2008, Nucleic acids research.

[53]  N. Gemmell,et al.  Conservation of Human Microsatellites across 450 Million Years of Evolution , 2010, Genome biology and evolution.

[54]  A. Rustighi,et al.  A polypyrimidine/polypurine tract within the Hmga2 minimal promoter: a common feature of many growth-related genes. , 2002, Biochemistry.

[55]  Xianjin Zhou,et al.  Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C , 1995, Nature.

[56]  S. Yip,et al.  Association of PAX6 polymorphisms with high myopia in Han Chinese nuclear families. , 2009, Investigative ophthalmology & visual science.

[57]  D. Loesch,et al.  Unstable mutations in the FMR1 gene and the phenotypes. , 2012, Advances in experimental medicine and biology.

[58]  J. Blackwell,et al.  Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility , 1999, Journal of medical genetics.

[59]  T. Mori,et al.  Destabilization of nucleosomes by an unusual DNA conformation adopted by poly(dA)·poly(dT) tracts in vivo , 2000 .

[60]  D. Leach,et al.  Secondary structures in d(CGG) and d(CCG) repeat tracts. , 1998, Journal of molecular biology.

[61]  S. Israel,et al.  Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA , 2008, Genes, brain, and behavior.

[62]  Matthieu Legendre,et al.  Unstable Tandem Repeats in Promoters Confer Transcriptional Evolvability , 2009, Science.

[63]  J. Jurka,et al.  Microsatellites in different eukaryotic genomes: survey and analysis. , 2000, Genome research.

[64]  Tom R. Gaunt,et al.  Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height. , 2011, American journal of human genetics.

[65]  R. Wells,et al.  Topoisomerase mutants and physiological conditions control supercoiling and Z-DNA formation in vivo. , 1991, The Journal of biological chemistry.

[66]  N. Gemmell,et al.  Measuring Microsatellite Conservation in Mammalian Evolution with a Phylogenetic Birth–Death Model , 2012, Genome biology and evolution.

[67]  P. Vourc'h,et al.  A functional tetranucleotide (AAAT) polymorphism in an Alu element in the NF1 gene is associated with mental retardation , 2011, Neuroscience Letters.

[68]  Karolin Luger,et al.  Nucleosome core particles containing a poly(dA.dT) sequence element exhibit a locally distorted DNA structure. , 2006, Journal of molecular biology.

[69]  Larry J Young,et al.  Microsatellite Instability Generates Diversity in Brain and Sociobehavioral Traits , 2005, Science.

[70]  Y. Kashi,et al.  Simple sequence repeats as advantageous mutators in evolution. , 2006, Trends in genetics : TIG.

[71]  K. Lesch,et al.  Regulation of PAX-6 gene transcription: alternate promoter usage in human brain. , 1998, Brain research. Molecular brain research.

[72]  B. Suter,et al.  Poly(dA.dT) sequences exist as rigid DNA structures in nucleosome-free yeast promoters in vivo. , 2000, Nucleic acids research.

[73]  L. Naylor,et al.  d(TG)n.d(CA)n sequences upstream of the rat prolactin gene form Z-DNA and inhibit gene transcription. , 1990, Nucleic acids research.

[74]  J. Yim,et al.  The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans , 2006, Genes and Immunity.

[75]  P. Rashbass,et al.  Influence of PAX6 Gene Dosage on Development: Overexpression Causes Severe Eye Abnormalities , 1996, Cell.

[76]  D. King Evolution of simple sequence repeats as mutable sites. , 2012, Advances in experimental medicine and biology.

[77]  S. Elgin,et al.  The capacity to form H-DNA cannot substitute for GAGA factor binding to a (CT)n*(GA)n regulatory site. , 2003, Nucleic acids research.

[78]  J. Streelman,et al.  Microsatellite variation associated with prolactin expression and growth of salt-challenged tilapia. , 2002, Physiological genomics.

[79]  P. Onkamo,et al.  Musical Aptitude Is Associated with AVPR1A-Haplotypes , 2009, PloS one.

[80]  Y. Xu,et al.  Recruitment of SWI/SNF Complex Is Required for Transcriptional Activation of the SLC11A1 Gene during Macrophage Differentiation of HL-60 Cells* , 2011, The Journal of Biological Chemistry.

[81]  A. Rich,et al.  Transcription is associated with Z-DNA formation in metabolically active permeabilized mammalian cell nuclei. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[82]  L. Borrmann,et al.  Human HMGA2 promoter is coregulated by a polymorphic dinucleotide (TC)-repeat , 2003, Oncogene.

[83]  G. Schroth,et al.  Mapping Z-DNA in the human genome. Computer-aided mapping reveals a nonrandom distribution of potential Z-DNA-forming sequences in human genes. , 1992, The Journal of biological chemistry.

[84]  M. Götz,et al.  The role of Pax6 in restricting cell migration between developing cortex and basal ganglia. , 1999, Development.

[85]  K. Itoh,et al.  BRG1 Interacts with Nrf2 To Selectively Mediate HO-1 Induction in Response to Oxidative Stress , 2006, Molecular and Cellular Biology.

[86]  Navneet Matharu,et al.  Vertebrate homologue of Drosophila GAGA factor. , 2010, Journal of molecular biology.

[87]  Christian Dina,et al.  AVPR1a and SLC6A4 Gene Polymorphisms Are Associated with Creative Dance Performance , 2005, PLoS genetics.

[88]  C. Wadelius,et al.  Two polypyrimidine tracts in the nitric oxide synthase 2 gene: similar regulatory sequences with different properties , 2010, Molecular Biology Reports.

[89]  S. Elgin,et al.  (CT)n (GA)n repeats and heat shock elements have distinct roles in chromatin structure and transcriptional activation of the Drosophila hsp26 gene , 1993, Molecular and cellular biology.

[90]  E. Segal,et al.  Poly(da:dt) Tracts: Major Determinants of Nucleosome Organization This Review Comes from a Themed Issue on Protein-nucleic Acid Interactions Edited , 2022 .

[91]  A. Rich,et al.  A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[92]  A. Kimura,et al.  Transcriptional regulation of the human type I collagen alpha2 (COL1A2) gene by the combination of two dinucleotide repeats. , 1999, Gene.

[93]  S. Tyekucheva,et al.  The genome-wide determinants of human and chimpanzee microsatellite evolution. , 2007, Genome research.

[94]  Y. Sasaguri,et al.  Shortened microsatellite d(CA)21 sequence down‐regulates promoter activity of matrix metalloproteinase 9 gene , 1999, FEBS letters.

[95]  K. Zänker,et al.  Modulation of Epidermal Growth Factor Receptor Gene Transcription by a Polymorphic Dinucleotide Repeat in Intron 1* , 1999, The Journal of Biological Chemistry.

[96]  V. Kulish,et al.  Z-DNA-induced super-transport of energy within genomes , 2007 .

[97]  A. Bernstein,et al.  An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes , 1995, Molecular and cellular biology.

[98]  Heng Li,et al.  Human genomic Z-DNA segments probed by the Zα domain of ADAR1 , 2009, Nucleic acids research.

[99]  S. Hannenhalli,et al.  Position and distance specificity are important determinants of cis-regulatory motifs in addition to evolutionary conservation , 2007, Nucleic acids research.

[100]  T. Petes,et al.  Control of Meiotic Recombination and Gene Expression in Yeast by a Simple Repetitive DNA Sequence That Excludes Nucleosomes , 1999, Molecular and Cellular Biology.

[101]  A. Goodridge,et al.  A CT repeat in the promoter of the chicken malic enzyme gene is essential for function at an alternative transcription start site. , 1998, Archives of biochemistry and biophysics.

[102]  P. Manunta,et al.  CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity. , 2000, Hypertension.

[103]  L. O'Brien,et al.  Influence of a GT repeat element on shear stress responsiveness of the VWF gene promoter , 2008, Journal of thrombosis and haemostasis : JTH.

[104]  S. Carson,et al.  Phase variation of the gonococcal siderophore receptor FetA , 2000, Molecular microbiology.

[105]  K. Zhao,et al.  Cooperative Activity of BRG1 and Z-DNA Formation in Chromatin Remodeling , 2006, Molecular and Cellular Biology.

[106]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[107]  D. Levens,et al.  The functional response of upstream DNA to dynamic supercoiling in vivo , 2008, Nature Structural &Molecular Biology.

[108]  C. Freitag,et al.  Association of a functional variant of neuronal nitric oxide synthase gene with self-reported impulsiveness, venturesomeness and empathy in male offenders , 2010, Journal of Neural Transmission.

[109]  M. Castellazzi,et al.  v-Jun downregulates the SPARC target gene by binding to the proximal promoter indirectly through Sp1/3 , 2003, Oncogene.

[110]  Yoo-Jeong Han,et al.  Naturally Extended CT · AG Repeats Increase H-DNA Structures and Promoter Activity in the Smooth Muscle Myosin Light Chain Kinase Gene , 2007, Molecular and Cellular Biology.

[111]  P. Reitsma,et al.  Unique distance- and DNA-turn-dependent interactions in the human protein C gene promoter confer submaximal transcriptional activity , 1999 .

[112]  G. Wray,et al.  Abundant raw material for cis-regulatory evolution in humans. , 2002, Molecular biology and evolution.

[113]  K. Lesch,et al.  Functional characterization of the human PAX3 gene regulatory region. , 1999, Genomics.

[114]  E. Hattori,et al.  Transcriptional activities of cholecystokinin promoter haplotypes and their relevance to panic disorder susceptibility , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[115]  K. Struhl Naturally occurring poly(dA-dT) sequences are upstream promoter elements for constitutive transcription in yeast. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[116]  R. Sinden,et al.  A Z-DNA sequence reduces slipped-strand structure formation in the myotonic dystrophy type 2 (CCTG)·(CAGG) repeat , 2009, Proceedings of the National Academy of Sciences.

[117]  W. Pan,et al.  Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients , 2002, Human Genetics.

[118]  M. Katahira,et al.  An intramolecular quadruplex of (GGA)(4) triplet repeat DNA with a G:G:G:G tetrad and a G(:A):G(:A):G(:A):G heptad, and its dimeric interaction. , 2001, Journal of molecular biology.

[119]  L. J. Peck,et al.  Transcriptional block caused by a negative supercoiling induced structural change in an alternating CG sequence , 1985, Cell.

[120]  K. Lesch,et al.  A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain. , 1998, Biochemical and biophysical research communications.

[121]  C. Lee,et al.  Dinucleotide repeats negatively modulate the promoter activity of Cyr61 and is unstable in hepatocellular carcinoma patients , 2005, Oncogene.