Cellular and Molecular Life Sciences

, Volume 75, Issue 7, pp 1205–1214 | Cite as

The emerging roles for the chromatin structure regulators CTCF and cohesin in neurodevelopment and behavior

Review
First Online:
Received:
Revised:
Accepted:

Abstract

Recent genetic and technological advances have determined a role for chromatin structure in neurodevelopment. In particular, compounding evidence has established roles for CTCF and cohesin, two elements that are central in the establishment of chromatin structure, in proper neurodevelopment and in regulation of behavior. Genetic aberrations in CTCF, and in subunits of the cohesin complex, have been associated with neurodevelopmental disorders in human genetic studies, and subsequent animal studies have established definitive, although sometime opposing roles, for these factors in neurodevelopment and behavior. Considering the centrality of these factors in cellular processes in general, the mechanisms through which dysregulation of CTCF and cohesin leads specifically to neurological phenotypes is intriguing, although poorly understood. The connection between CTCF, cohesin, chromatin structure, and behavior is likely to be one of the next frontiers in our understanding of the development of behavior in general, and neurodevelopmental disorders in particular.

Keywords

CTCF Cohesin Condensin Neurodevelopment Chromatin structure Behavior Intellectual disability SMC 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

We would like to thank Anita Impagliazzo for providing professional graphical support in preparing the figure for this manuscript. This study has been supported by Israel Science Foundation Grant 1099/16 (I.O) and Israel Science Foundation Grant 898/17 (E.E).

References

  1. 1.
    Gonzalez-Sandoval A, Gasser SM (2016) On tads and lads: spatial control over gene expression. Trends Genet 32:485–495CrossRefPubMedGoogle Scholar
  2. 2.
    Du Z, Zheng H, Huang B, Ma R, Wu J, Zhang X, He J, Xiang Y, Wang Q, Li Y et al (2017) Allelic reprogramming of 3D chromatin architecture during early mammalian development. Nature 547:232–235CrossRefPubMedGoogle Scholar
  3. 3.
    Flyamer IM, Gassler J, Imakaev M, Brandão HB, Ulianov SV, Abdennur N, Razin SV, Mirny LA, Tachibana-Konwalski K (2017) Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544:110–114CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Aoto T, Saitoh N, Ichimura T, Niwa H, Nakao M (2006) Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation. Dev Biol 298:354–367CrossRefPubMedGoogle Scholar
  5. 5.
    Le Gros MA, Clowney EJ, Magklara A, Yen A, Markenscoff-Papadimitriou E, Colquitt B, Myllys M, Kellis M, Lomvardas S, Larabell CA (2016) Soft X-ray tomography reveals gradual chromatin compaction and reorganization during neurogenesis in vivo. Cell Rep 17:2125–2136CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Won H, de la Torre-Ubieta L, Stein JL, Parikshak NN, Huang J, Opland CK, Gandal MJ, Sutton GJ, Hormozdiari F, Lu D et al (2016) Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538:523–527CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jiang Y, Loh YE, Rajarajan P, Hirayama T, Liao W, Kassim BS, Javidfar B, Hartley BJ, Kleofas L, Park RB et al (2017) The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nat Genet 49:1239–1250CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bao L, Zhou M, Cui Y (2008) CTCFBSDB: a CTCF-binding site database for characterization of vertebrate genomic insulators. Nucleic Acids Res 36:D83–D87CrossRefPubMedGoogle Scholar
  9. 9.
    Klenova EM, Nicolas RH, Paterson HF, Carne AF, Heath CM, Goodwin GH, Neiman PE, Lobanenkov VV (1993) CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol Cell Biol 13:7612–7624CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Nasmyth K, Haering CH (2009) Cohesin: its roles and mechanisms. Annu Rev Genet 43:525–558CrossRefPubMedGoogle Scholar
  11. 11.
    Wendt KS, Peters JM (2009) How cohesin and CTCF cooperate in regulating gene expression. Chromosome Res 17:201–214CrossRefPubMedGoogle Scholar
  12. 12.
    Lee BK, Iyer VR (2012) Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation. J Biol Chem 287:30906–30913CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Onn I, Heidinger-Pauli JM, Guacci V, Unal E, Koshland DE (2008) Sister chromatid cohesion: a simple concept with a complex reality. Annu Rev Cell Dev Biol 24:105–129CrossRefPubMedGoogle Scholar
  14. 14.
    Rana V, Bosco G (2017) Condensin regulation of genome architecture. J Cell Physiol 232:1617–1625CrossRefPubMedGoogle Scholar
  15. 15.
    Kalitsis P, Zhang T, Marshall KM, Nielsen CF, Hudson DF (2017) Condensin, master organizer of the genome. Chromosome Res 25:61–76CrossRefPubMedGoogle Scholar
  16. 16.
    Dolgin E (2017) DNA’s secret weapon against knots and tangles. Nature 544:284–286CrossRefPubMedGoogle Scholar
  17. 17.
    Zuin J, Dixon JR, van der Reijden MI, Ye Z, Kolovos P, Brouwer RW, van de Corput MP, van de Werken HJ, Knoch TA, van IJcken wf et al (2014) Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci USA 111:996–1001CrossRefPubMedGoogle Scholar
  18. 18.
    Yuen KC, Slaughter BD, Gerton JL (2017) Condensin II is anchored by TFIIIC and H3K4me3 in the mammalian genome and supports the expression of active dense gene clusters. Sci Adv 3:e1700191CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Donohoe ME, Zhang LF, Xu N, Shi Y, Lee JT (2007) Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch. Mol Cell 25:43–56CrossRefPubMedGoogle Scholar
  20. 20.
    Liu Z, Scannell DR, Eisen MB, Tjian R (2011) Control of embryonic stem cell lineage commitment by core promoter factor, TAF3. Cell 146:720–731CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Marsman J, O’Neill AC, Kao BR, Rhodes JM, Meier M, Antony J, Mönnich M, Horsfield JA (2014) Cohesin and CTCF differentially regulate spatiotemporal runx1 expression during zebrafish development. Biochim Biophys Acta 1839:50–61CrossRefPubMedGoogle Scholar
  22. 22.
    Gregor A, Oti M, Kouwenhoven EN, Hoyer J, Sticht H, Ekici AB, Kjaergaard S, Rauch A, Stunnenberg HG, Uebe S et al (2013) De novo mutations in the genome organizer CTCF cause intellectual disability. Am J Hum Genet 93:124–131CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bastaki F, Nair P, Mohamed M, Malik EM, Helmi M, Al-Ali MT, Hamzeh AR (2017) Identification of a novel CTCF mutation responsible for syndromic intellectual disability—a case report. BMC Med Genet 18:68CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Juraeva D, Haenisch B, Zapatka M, Frank J, GROUP Investigators, PSYCH-GEMS SCZ Working Group, Witt SH, Mühleisen TW, Treutlein J, Strohmaier J et al (2014) Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia. PLoS Genet 10:e1004345Google Scholar
  25. 25.
    Mannini L, Cucco F, Quarantotti V, Krantz ID, Musio A (2013) Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome. Hum Mutat 34:1589–1596CrossRefPubMedGoogle Scholar
  26. 26.
    Deardorff MA, Noon SE, Krantz ID (1993) Cornelia de lange syndrome. In: GeneReviews(®), Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH et al (eds). University of Washington, SeattleGoogle Scholar
  27. 27.
    Alomer RM, da Silva EML, Chen J, Piekarz KM, McDonald K, Sansam CG, Sansam CL, Rankin S (2017) Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression. Proc Natl Acad Sci USA 114:9906–9911CrossRefPubMedGoogle Scholar
  28. 28.
    Gordillo M, Vega H, Jabs EW (1993) Roberts Syndrome. In GeneReviews(®), Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH et al (eds).University of Washington, SeattleGoogle Scholar
  29. 29.
    Rudra S, Skibbens RV (2013) Chl1 DNA helicase regulates Scc2 deposition specifically during DNA-replication in Saccharomyces cerevisiae. PLoS One 8:e75435CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Banerji R, Skibbens RV, Iovine MK (2017) How many roads lead to cohesinopathies? Dev Dyn 246(11): 881–888CrossRefPubMedGoogle Scholar
  31. 31.
    Cucco F, Musio A (2016) Genome stability: what we have learned from cohesinopathies. Am J Med Genet C Semin Med Genet 172:171–178CrossRefPubMedGoogle Scholar
  32. 32.
    Martin CA, Murray JE, Carroll P, Leitch A, Mackenzie KJ, Halachev M, Fetit AE, Keith C, Bicknell LS, Fluteau A et al (2016) Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis. Genes Dev 30:2158–2172CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    De Biase I, Chutake YK, Rindler PM, Bidichandani SI (2009) Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription. PLoS One 4:e7914CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Al-Mahdawi S, Sandi C, Mouro Pinto R, Pook MA (2013) Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus. PLoS One 8:e74956CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jajodia A, Singh KD, Singhal A, Vig S, Datta M, Singh Y, Karthikeyan M, Kukreti R (2015) Methylation of a HTR3A promoter variant alters the binding of transcription factor CTCF. RSC Adv 5:45710–45717CrossRefGoogle Scholar
  36. 36.
    De Souza RA, Islam SA, McEwen LM, Mathelier A, Hill A, Mah SM, Wasserman WW, Kobor MS, Leavitt BR (2016) DNA methylation profiling in human Huntington’s disease brain. Hum Mol Genet 25:2013–2030CrossRefPubMedGoogle Scholar
  37. 37.
    Naumann A, Kraus C, Hoogeveen A, Ramirez CM, Doerfler W (2014) Stable DNA methylation boundaries and expanded trinucleotide repeats: role of DNA insertions. J Mol Biol 426:2554–2566CrossRefPubMedGoogle Scholar
  38. 38.
    Lanni S, Goracci M, Borrelli L, Mancano G, Chiurazzi P, Moscato U, Ferrè F, Helmer-Citterich M, Tabolacci E, Neri G (2013) Role of CTCF protein in regulating FMR1 locus transcription. PLoS Genet 9:e1003601CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188CrossRefPubMedGoogle Scholar
  40. 40.
    Kernohan KD, Vernimmen D, Gloor GB, Bérubé NG (2014) Analysis of neonatal brain lacking ATRX or MeCP2 reveals changes in nucleosome density, CTCF binding and chromatin looping. Nucleic Acids Res 42:8356–8368CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kernohan KD, Jiang Y, Tremblay DC, Bonvissuto AC, Eubanks JH, Mann MR, Bérubé NG (2010) ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain. Dev Cell 18:191–202CrossRefPubMedGoogle Scholar
  42. 42.
    Gibbons RJ, Picketts DJ, Villard L, Higgs DR (1995) Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell 80:837–845CrossRefPubMedGoogle Scholar
  43. 43.
    Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT et al (2014) Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158:263–276CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ishihara K, Oshimura M, Nakao M (2006) CTCF-dependent chromatin insulator is linked to epigenetic remodeling. Mol Cell 23:733–742CrossRefPubMedGoogle Scholar
  45. 45.
    Shi L, Li M, Lin Q, Qi X, Su B (2013) Functional divergence of the brain-size regulating gene MCPH1 during primate evolution and the origin of humans. BMC Biol 11:62CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Trimborn M, Schindler D, Neitzel H, Hirano T (2006) Misregulated chromosome condensation in MCPH1 primary microcephaly is mediated by condensin II. Cell Cycle 5:322–326CrossRefPubMedGoogle Scholar
  47. 47.
    Heath H, Ribeiro de Almeida C, Sleutels F, Dingjan G, van de Nobelen S, Jonkers I, Ling KW, Gribnau J, Renkawitz R, Grosveld F et al (2008) CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J 27:2839–2850CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Hirayama T, Tarusawa E, Yoshimura Y, Galjart N, Yagi T (2012) CTCF is required for neural development and stochastic expression of clustered Pcdh genes in neurons. Cell Rep 2:345–357CrossRefPubMedGoogle Scholar
  49. 49.
    Moore JM, Rabaia NA, Smith LE, Fagerlie S, Gurley K, Loukinov D, Disteche CM, Collins SJ, Kemp CJ, Lobanenkov VV et al (2012) Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos. PLoS One 7:e34915CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Watson LA, Wang X, Elbert A, Kernohan KD, Galjart N, Bérubé NG (2014) Dual effect of CTCF loss on neuroprogenitor differentiation and survival. J Neurosci 34:2860–2870CrossRefPubMedGoogle Scholar
  51. 51.
    Sams DS, Nardone S, Getselter D, Raz D, Tal M, Rayi PR, Kaphzan H, Hakim O, Elliott E (2016) Neuronal CTCF is necessary for basal and experience-dependent gene regulation, memory formation, and genomic structure of BDNF and arc. Cell Rep 17:2418–2430CrossRefPubMedGoogle Scholar
  52. 52.
    Bharadwaj R, Peter CJ, Jiang Y, Roussos P, Vogel-Ciernia A, Shen EY, Mitchell AC, Mao W, Whittle C, Dincer A et al (2014) Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron 84:997–1008CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Engmann O, Labonté B, Mitchell A, Bashtrykov P, Calipari ES, Rosenbluh C, Loh YE, Walker DM, Burek D, Hamilton PJ et al. (2017) Cocaine-induced chromatin modifications associate with increased expression and three-dimensional looping of Auts2. Biol Psychiatry 82(11):794–805CrossRefPubMedGoogle Scholar
  54. 54.
    Aguilar-Arnal L, Hakim O, Patel VR, Baldi P, Hager GL, Sassone-Corsi P (2013) Cycles in spatial and temporal chromosomal organization driven by the circadian clock. Nat Struct Mol Biol 20:1206–1213CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Schuldiner O, Berdnik D, Levy JM, Wu JS, Luginbuhl D, Gontang AC, Luo L (2008) piggyBac-based mosaic screen identifies a postmitotic function for cohesin in regulating developmental axon pruning. Dev Cell 14:227–238CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Singh VP, Gerton JL (2015) Cohesin and human disease: lessons from mouse models. Curr Opin Cell Biol 37:9–17CrossRefPubMedGoogle Scholar
  57. 57.
    Remeseiro S, Cuadrado A, Gómez-López G, Pisano DG, Losada A (2012) A unique role of cohesin-SA1 in gene regulation and development. EMBO J 31:2090–2102CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Fujita Y, Masuda K, Bando M, Nakato R, Katou Y, Tanaka T, Nakayama M, Takao K, Miyakawa T, Tanaka T et al (2017) Decreased cohesin in the brain leads to defective synapse development and anxiety-related behavior. J Exp Med 214:1431–1452CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Monahan K, Rudnick ND, Kehayova PD, Pauli F, Newberry KM, Myers RM, Maniatis T (2012) Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-α gene expression. Proc Natl Acad Sci USA 109:9125–9130CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Hirabayashi T, Yagi T (2014) Protocadherins in neurological diseases. Adv Neurobiol 8:293–314CrossRefPubMedGoogle Scholar
  61. 61.
    Van den Berg DL, Azzarelli R, Oishi K, Martynoga B, Urbán N, Dekkers DH, Demmers JA, Guillemot F (2017) Nipbl Interacts with Zfp609 and the integrator complex to regulate cortical neuron migration. Neuron 93:348–361CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Houlihan SL, Feng Y (2014) The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation. elife 3:e03297CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Ou HD, Phan S, Deerinck TJ, Thor A, Ellisman MH, O’Shea CC (2017) ChromEMT: visualizing 3D chromatin structure and compaction in interphase and mitotic cells. Science 357:eaag0025CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Beagrie RA, Scialdone A, Schueler M, Kraemer DC, Chotalia M, Xie SQ, Barbieri M, de Santiago I, Lavitas LM, Branco MR et al (2017) Complex multi-enhancer contacts captured by genome architecture mapping. Nature 543:519–524CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Stevens TJ, Lando D, Basu S, Atkinson LP, Cao Y, Lee SF, Leeb M, Wohlfahrt KJ, Boucher W, O’Shaughnessy-Kirwan A et al (2017) 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature 544:59–64CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Boyle MI, Jespersgaard C, Brøndum-Nielsen K, Bisgaard AM, Tümer Z (2015) Cornelia de Lange syndrome. Clin Genet 88:1–12CrossRefPubMedGoogle Scholar
  67. 67.
    Vega H, Waisfisz Q, Gordillo M, Sakai N, Yanagihara I, Yamada M, van Gosliga D, Kayserili H, Xu C, Ozono K et al (2005) Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat Genet 37(5):468–470CrossRefPubMedGoogle Scholar
  68. 68.
    Capo-Chichi JM, Bharti SK, Sommers JA, Yammine T, Chouery E, Patry L, Rouleau GA, Samuels ME, Hamdan FF, Michaud JL et al (2013) Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. Hum Mutat 34:103–107CrossRefPubMedGoogle Scholar
  69. 69.
    Van der Lelij P, Chrzanowska KH, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, Zdzienicka MZ, Joenje H, de Winter JP (2010) Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am J Hum Genet 86:262–266CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kawauchi S, Calof AL, Santos R, Lopez-Burks ME, Young CM, Hoang MP, Chua A, Lao T, Lechner MS, Daniel JA et al (2009) Multiple organ system defects and transcriptional dysregulation in the Nipbl(±) mouse, a model of Cornelia de Lange Syndrome. PLoS Genet 5:e1000650CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Molecular and Behavioral Neurosciences Laboratory, Faculty of Medicine in the GalileeBar-Ilan UniversitySafedIsrael
  2. 2.Chromosome Instability and Dynamics Laboratory, Faculty of Medicine in the GalileeBar-Ilan UniversitySafedIsrael

Personalised recommendations