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Dynamic Lamin B1-Gene Association During Oligodendrocyte Progenitor Differentiation

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Abstract

Differentiation of oligodendrocytes (OL) from progenitor cells (OPC) is the result of a unique program of gene expression, which is further regulated by the formation of topological domains of association with the nuclear lamina. In this study, we show that cultured OPC were characterized by progressively declining levels of endogenous Lamin B1 (LMNB1) during differentiation into OL. We then identify the genes dynamically associated to the nuclear lamina component LMNB1 during this transition, using a well established technique called DamID, which is based on the ability of a bacterially-derived deoxyadenosine methylase (Dam), to modify genomic regions in close proximity. We expressed a fusion protein containing Dam and LMNB1 in OPC (OPCLMNB1-Dam) and either kept them proliferating or differentiated them into OL (OLLMNB1-Dam) and identified genes that were dynamically associated to LMNB1 with differentiation. Importantly, we identified Lss, the gene encoding for lanosterol synthase, a key enzyme in cholesterol synthesis, as associated to the nuclear lamina in OLLMNB1-Dam. This finding could at least in part explain the lipid dysregulation previously reported for mouse models of ADLD characterized by persistent LMNB1 expression in oligodendrocytes.

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References

  1. 1.

    Young RA (2011) Control of the embryonic stem cell state. Cell 144:940–954. https://doi.org/10.1016/j.cell.2011.01.032

  2. 2.

    Zaret KS, Carroll JS (2011) Pioneer transcription factors : establishing competence for gene expression Parameters affecting transcription factor access to target sites in chromatin Initiating events in chromatin : pioneer factors bind first. Genes Dev. https://doi.org/10.1101/gad.176826.111.GENES

  3. 3.

    Mohn F, Schübeler D (2009) Genetics and epigenetics: stability and plasticity during cellular differentiation. Trends Genet 25:129–136. https://doi.org/10.1016/j.tig.2008.12.005

  4. 4.

    Catalanotto C, Cogoni C, Zardo G (2016) MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci. https://doi.org/10.3390/ijms17101712

  5. 5.

    Li G, Reinberg D (2011) Chromatin higher-order structures and gene regulation. Curr Opin Genet Dev 21:175–186. https://doi.org/10.1016/j.gde.2011.01.022

  6. 6.

    Peric-Hupkes D, Meuleman W, Pagie L et al (2010) Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol Cell. https://doi.org/10.1016/j.molcel.2010.03.016

  7. 7.

    Dittmer T, Misteli T (2011) The lamin protein family. Genome Biol. https://doi.org/10.1186/gb-2011-12-5-222

  8. 8.

    Jung H-J, Nobumori C, Goulbourne CN et al (2013) Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration. Proc Natl Acad Sci USA 110:E1923–E1932. https://doi.org/10.1073/pnas.1303916110

  9. 9.

    Dechat T, Pfleghaar K, Sengupta K et al (2008) Nuclear lamins: Major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 22:832–853. https://doi.org/10.1101/gad.1652708

  10. 10.

    Gonzalo S (2014) DNA Damage and Lamins. In: Schirmer EC, de las Heras JI (eds) Cancer biology and the nuclear envelope. Advances in experimental medicine and biology, vol 773. Springer, pp 377–399

  11. 11.

    Butin-Israeli V, Adam SA, Jain N et al (2015) Role of lamin B1 in chromatin instability. Mol Cell Biol 35:884–898. https://doi.org/10.1128/mcb.01145-14

  12. 12.

    Andrés V, González JM (2009) Role of A-type lamins in signaling, transcription, and chromatin organization. J Cell Biol 187:945–957. https://doi.org/10.1083/jcb.200904124

  13. 13.

    Camozzi D, Capanni C, Cenni V, et al (2014) Diverse lamin-dependent mechanisms interact to control chromatin dynamics. Nucleus 5(5):427–440

  14. 14.

    Naetar N, Ferraioli S, Foisner R (2017) Lamins in the nuclear interior—life outside the lamina. J Cell Sci 130:2087–2096. https://doi.org/10.1242/jcs.203430

  15. 15.

    Swift J, Ivanovska IL, Buxboim A, et al (2013) Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science (80- ) 341:. https://doi.org/10.1126/science.1240104

  16. 16.

    Swift J, Discher DE (2014) The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue. J Cell Sci 127:3005–3015. https://doi.org/10.1242/jcs.149203

  17. 17.

    Lochs SJA, Kefalopoulou S, Kind J (2019) Lamina associated domains and gene regulation in development and cancer. Cells 8:271. https://doi.org/10.3390/cells8030271

  18. 18.

    Dechat T, Adam SA, Taimen P et al (2010) Nuclear lamins (review). Cold Spring Harb Perspect Biol 2:1–23. https://doi.org/10.1101/cshperspect.a000547

  19. 19.

    Takamori Y, Hirahara Y, Wakabayashi T et al (2018) Differential expression of nuclear lamin subtypes in the neural cells of the adult rat cerebral cortex. IBRO Rep 5:99–109. https://doi.org/10.1016/j.ibror.2018.11.001

  20. 20.

    Coffeen CM (2000) Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31. Hum Mol Genet 9:787–793. https://doi.org/10.1093/hmg/9.5.787

  21. 21.

    Padiath QS, Saigoh K, Schiffmann R et al (2006) Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 38:1114–1123. https://doi.org/10.1038/ng1872

  22. 22.

    Padiath QS (2016) Lamin B1 mediated demyelination: linking lamins, lipids and leukodystrophies. Nucleus 7:547–553. https://doi.org/10.1080/19491034.2016.1260799

  23. 23.

    Lin S-T, Fu Y-H (2009) miR-23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination. Dis Model Mech 2:178–188. https://doi.org/10.1242/dmm.001065

  24. 24.

    Giorgio E, Robyr D, Spielmann M et al (2014) A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD). Hum Mol Genet 24:3143–3154. https://doi.org/10.1093/hmg/ddv065

  25. 25.

    Rolyan H, Nmezi BC, Chen J et al (2015) Defects of lipid synthesis are linked to the age-dependent demyelination caused by Lamin B1 overexpression. J Neurosci 35:2002–12017. https://doi.org/10.1523/JNEUROSCI.1668-15.2015

  26. 26.

    Heng MY, Lin ST, Verret L et al (2013) Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. J Clin Invest 123:2719–2729. https://doi.org/10.1172/JCI66737

  27. 27.

    Steensel B Van, Henikoff S (2000) Steensel.Henikoff.DamID.NatBiotech.2000. 18

  28. 28.

    Vogel MJ, Peric-Hupkes D, van Steensel B (2007) Detection of in vivo protein - DNA interactions using DamID in mammalian cells. Nat Protoc 2:1467–1478. https://doi.org/10.1038/nprot.2007.148

  29. 29.

    Scaglione A, Patzig J, Liang J et al (2018) PRMT5-mediated regulation of developmental myelination. Nat Commun. https://doi.org/10.1038/s41467-018-04863-9

  30. 30.

    Li H, Durbin R (2010) Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26:589–595. https://doi.org/10.1093/bioinformatics/btp698

  31. 31.

    Day N, Hemmaplardh A, Thurman RE et al (2007) Unsupervised segmentation of continuous genomic data. Bioinformatics 23:1424–1426. https://doi.org/10.1093/bioinformatics/btm096

  32. 32.

    Karolchik D (2003) The UCSC Table Browser data retrieval tool. Nucleic Acids Res 32:493D–496. https://doi.org/10.1093/nar/gkh103

  33. 33.

    Zhang Y, Chen K, Sloan SA et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947. https://doi.org/10.1523/jneurosci.1860-14.2014

  34. 34.

    Sharma K, Schmitt S, Bergner CG et al (2015) Cell type- and brain region-resolved mouse brain proteome. Nat Neurosci 18:1819–1831. https://doi.org/10.1038/nn.4160

  35. 35.

    McKenzie AT, Wang M, Hauberg ME et al (2018) Brain cell type specific gene expression and co-expression network architectures. Sci Rep 8:1–19. https://doi.org/10.1038/s41598-018-27293-5

  36. 36.

    Chen EY, Tan CM, Kou Y et al (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform. https://doi.org/10.1186/1471-2105-14-128

  37. 37.

    Kuleshov MV, Jones MR, Rouillard AD et al (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44:W90–W97. https://doi.org/10.1093/nar/gkw377

  38. 38.

    Gorkin DU, Leung D, Ren B (2014) The 3D genome in transcriptional regulation and pluripotency. Cell Stem Cell 14:762–775. https://doi.org/10.1016/j.stem.2014.05.017

  39. 39.

    Wu YQ, Lin X, Liu CM et al (2001) Identification of a human brain-specific gene, calneuron 1, a new member of the calmodulin superfamily. Mol Genet Metab 72:343–350. https://doi.org/10.1006/mgme.2001.3160

  40. 40.

    Swiss VA, Nguyen T, Dugas J et al (2011) Identification of a gene regulatory network necessary for the initiation of oligodendrocyte differentiation. PLoS ONE. https://doi.org/10.1371/journal.pone.0018088

  41. 41.

    Van Den KR, Raymond Y, Ramaekers FCS et al (1997) A- and B-type lamins are differentially expressed in normal human tissues. Histochem Cell Biol 107:505–517

  42. 42.

    Takamori Y, Tamura Y, Kataoka Y et al (2007) Differential expression of nuclear lamin, the major component of nuclear lamina, during neurogenesis in two germinal regions of adult rat brain. Eur J Neurosci 25:1653–1662. https://doi.org/10.1111/j.1460-9568.2007.05450.x

  43. 43.

    Giorgio E, Rolyan H, Kropp L et al (2013) Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression. Hum Mutat 34:1160–1171. https://doi.org/10.1002/humu.22348

  44. 44.

    Yu Y, Casaccia P, Richard LuQ (2010) Shaping the oligodendrocyte identity by epigenetic control. Epigenetics 5:124–128. https://doi.org/10.4161/epi.5.2.11160

  45. 45.

    Emery B (2010) Regulation of oligodendrocyte differentiation and myelination. Science (80-) 330:779–782. https://doi.org/10.1126/science.1190927

  46. 46.

    Gonzalez-Sandoval A, Gasser SM (2016) On TADs and LADs: spatial control over gene expression. Trends Genet 32:485–495. https://doi.org/10.1016/j.tig.2016.05.004

  47. 47.

    Pickersgill H, Kalverda B, De Wit E et al (2006) Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nat Genet 38:1005–1014. https://doi.org/10.1038/ng1852

  48. 48.

    Towbin BD, González-Aguilera C, Sack R et al (2012) Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150:934–947. https://doi.org/10.1016/j.cell.2012.06.051

  49. 49.

    Harr JC, Luperchio TR, Wong X et al (2015) Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins. J Cell Biol 208:33–52. https://doi.org/10.1083/jcb.201405110

  50. 50.

    Harr JC, Gonzalez‐Sandoval A, Gasser SM (2016) Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man. EMBO Rep 17:139–155. https://doi.org/10.15252/embr.201541809

  51. 51.

    Solovei I, Wang AS, Thanisch K et al (2013) LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152:584–598. https://doi.org/10.1016/j.cell.2013.01.009

  52. 52.

    van Steensel B, Belmont AS (2017) Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169:780–791. https://doi.org/10.1016/j.cell.2017.04.022

  53. 53.

    Meuleman W, Peric-Hupkes D, Kind J et al (2013) Constitutive nuclear lamina-genome interactions are highly conserved and associated with A/T-rich sequence. Genome Res 23:270–280. https://doi.org/10.1101/gr.141028.112

  54. 54.

    Yáñez-Cuna JO, van Steensel B (2017) Genome–nuclear lamina interactions: from cell populations to single cells. Curr Opin Genet Dev 43:67–72. https://doi.org/10.1016/j.gde.2016.12.005

  55. 55.

    Poleshko A, Shah PP, Gupta M et al (2017) Genome-nuclear lamina interactions regulate cardiac stem cell lineage restriction. Cell 171:573–587.e14. https://doi.org/10.1016/j.cell.2017.09.018

  56. 56.

    Gruenbaum Y, Foisner R (2015) Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annu Rev Biochem 84:131–164. https://doi.org/10.1146/annurev-biochem-060614-034115

  57. 57.

    Worman HJ, Bonne G (2007) “Laminopathies”: a wide spectrum of human diseases. Exp Cell Res 313:2121–2133. https://doi.org/10.1016/j.yexcr.2007.03.028

  58. 58.

    Dobrzynska A, Gonzalo S, Shanahan C, Askjaer P (2016) The nuclear lamina in health and disease. Nucleus 7:233–248. https://doi.org/10.1080/19491034.2016.1183848

  59. 59.

    Hegele RA, Cao H, Liu DM et al (2006) Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. Am J Hum Genet 79:383–389. https://doi.org/10.1086/505885

  60. 60.

    Damiano JA, Afawi Z, Bahlo M et al (2015) Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia. Hum Mol Genet 24:4483–4490. https://doi.org/10.1093/hmg/ddv171

  61. 61.

    van der Knaap MS, Bugiani M (2017) Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Springer, Berlin

  62. 62.

    Lo Martire V, Alvente S, Bastianini S et al (2018) Mice overexpressing lamin B1 in oligodendrocytes recapitulate the age-dependent motor signs, but not the early autonomic cardiovascular dysfunction of autosomal-dominant leukodystrophy (ADLD). Exp Neurol 301:1–12. https://doi.org/10.1016/j.expneurol.2017.12.006

  63. 63.

    Padiath QS (2019) Autosomal dominant leukodystrophy: a disease of the nuclear lamina. Front Cell Dev Biol 7:1–6. https://doi.org/10.3389/fcell.2019.00041

  64. 64.

    Moyon S, Liang J, Casaccia P (2016) Epigenetics in NG2 glia cells. Brain Res 1638:183–198. https://doi.org/10.1016/j.brainres.2015.06.009

  65. 65.

    Li H, He Y, Richardson WD, Casaccia P (2009) Two-tier transcriptional control of oligodendrocyte differentiation. Curr Opin Neurobiol 19:479–485. https://doi.org/10.1016/j.conb.2009.08.004

  66. 66.

    Liu J, Casaccia P (2010) Epigenetic regulation of oligodendrocyte identity. Trends Neurosci 33:193–201. https://doi.org/10.1016/j.tins.2010.01.007

  67. 67.

    Hernandez M, Casaccia P (2015) Interplay between transcriptional control and chromatin regulation in the oligodendrocyte lineage. Glia 63:1357–1375. https://doi.org/10.1002/glia.22818

  68. 68.

    Tsai E, Casaccia P (2019) Mechano-modulation of nuclear events regulating oligodendrocyte progenitor gene expression. Glia 67:1229–1239. https://doi.org/10.1002/glia.23595

  69. 69.

    Liu J, Moyon S, Hernandez M, Casaccia P (2016) Epigenetic control of oligodendrocyte development: Adding new players to old keepers. Curr Opin Neurobiol 39:133–138. https://doi.org/10.1016/j.conb.2016.06.002

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Acknowledgments

The authors would like to thank Drs. Bas van Steensel and Daan Peric-Hupkes for generous sharing of reagents and protocols and for providing invaluable suggestions. This work was supported by Grant R35 NS111604 to PC.

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Correspondence to Patrizia Casaccia.

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Yattah, C., Hernandez, M., Huang, D. et al. Dynamic Lamin B1-Gene Association During Oligodendrocyte Progenitor Differentiation. Neurochem Res (2020). https://doi.org/10.1007/s11064-019-02941-y

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Keywords

  • Nuclear lamina
  • Myelin
  • Brain
  • Leukodystrophy