CTCF-mediated Chromatin Looping in EGR2 Regulation and SUZ12 Recruitment Critical for Peripheral Myelination and Repair

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Aug 19

PMID 32807777

Citations 23

Authors

Jincheng Wang

Jiajia Wang

Lijun Yang

Chuntao Zhao

Laiman Natalie Wu

Lingli Xu

Feng Zhang

Qinjie Weng

Michael Wegner

Q Richard Lu

Affiliations

Soon will be listed here.

Abstract

Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. In this report, we demonstrate that the CCCTC-binding factor (CTCF), a crucial chromatin organizer, is essential for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of CTCF or its deletion blocks Schwann cell differentiation at the pro-myelinating stage, whereas overexpression of CTCF promotes the myelination program. We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2 (PRC2), to repress the transcriptional program associated with negative regulation of Schwann cell maturation. Together, our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block Schwann cell differentiation inhibitors to control peripheral myelination and repair.

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References

Li G, Reinberg D . Chromatin higher-order structures and gene regulation. Curr Opin Genet Dev. 2011; 21(2):175-86. PMC: 3124554. DOI: 10.1016/j.gde.2011.01.022. View

Kagey M, Newman J, Bilodeau S, Zhan Y, Orlando D, van Berkum N . Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010; 467(7314):430-5. PMC: 2953795. DOI: 10.1038/nature09380. View

Phillips J, Corces V . CTCF: master weaver of the genome. Cell. 2009; 137(7):1194-211. PMC: 3040116. DOI: 10.1016/j.cell.2009.06.001. View

Gregor A, Oti M, Kouwenhoven E, Hoyer J, Sticht H, Ekici A . De novo mutations in the genome organizer CTCF cause intellectual disability. Am J Hum Genet. 2013; 93(1):124-31. PMC: 3710752. DOI: 10.1016/j.ajhg.2013.05.007. View

Flavahan W, Drier Y, Liau B, Gillespie S, Venteicher A, Stemmer-Rachamimov A . Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2015; 529(7584):110-4. PMC: 4831574. DOI: 10.1038/nature16490. View

Pereira J, Lebrun-Julien F, Suter U . Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci. 2011; 35(2):123-34. DOI: 10.1016/j.tins.2011.11.006. View

Salzer J . Schwann cell myelination. Cold Spring Harb Perspect Biol. 2015; 7(8):a020529. PMC: 4526746. DOI: 10.1101/cshperspect.a020529. View

Jessen K, Mirsky R . The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 2005; 6(9):671-82. DOI: 10.1038/nrn1746. View

Jaegle M, Ghazvini M, Mandemakers W, Piirsoo M, Driegen S, Levavasseur F . The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development. Genes Dev. 2003; 17(11):1380-91. PMC: 196070. DOI: 10.1101/gad.258203. View

10.

Svaren J, Meijer D . The molecular machinery of myelin gene transcription in Schwann cells. Glia. 2008; 56(14):1541-1551. PMC: 2930200. DOI: 10.1002/glia.20767. View

11.

Topilko P, Schneider-Maunoury S, Levi G, Baron-Van Evercooren A, Chennoufi A, Seitanidou T . Krox-20 controls myelination in the peripheral nervous system. Nature. 1994; 371(6500):796-9. DOI: 10.1038/371796a0. View

12.

Nagarajan R, Svaren J, Le N, Araki T, Watson M, Milbrandt J . EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Neuron. 2001; 30(2):355-68. DOI: 10.1016/s0896-6273(01)00282-3. View

13.

Mirsky R, Woodhoo A, Parkinson D, Arthur-Farraj P, Bhaskaran A, Jessen K . Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation. J Peripher Nerv Syst. 2008; 13(2):122-35. DOI: 10.1111/j.1529-8027.2008.00168.x. View

14.

Woodhoo A, Alonso M, Droggiti A, Turmaine M, DAntonio M, Parkinson D . Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat Neurosci. 2009; 12(7):839-47. PMC: 2782951. DOI: 10.1038/nn.2323. View

15.

Jessen K, Mirsky R, Lloyd A . Schwann Cells: Development and Role in Nerve Repair. Cold Spring Harb Perspect Biol. 2015; 7(7):a020487. PMC: 4484967. DOI: 10.1101/cshperspect.a020487. View

16.

Braccioli L, de Wit E . CTCF: a Swiss-army knife for genome organization and transcription regulation. Essays Biochem. 2019; 63(1):157-165. DOI: 10.1042/EBC20180069. View

17.

Ong C, Corces V . CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet. 2014; 15(4):234-46. PMC: 4610363. DOI: 10.1038/nrg3663. View

18.

Merkenschlager M, Odom D . CTCF and cohesin: linking gene regulatory elements with their targets. Cell. 2013; 152(6):1285-97. DOI: 10.1016/j.cell.2013.02.029. View

19.

Zuin J, Dixon J, van der Reijden M, Ye Z, Kolovos P, Brouwer R . Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci U S A. 2013; 111(3):996-1001. PMC: 3903193. DOI: 10.1073/pnas.1317788111. View

20.

Splinter E, Heath H, Kooren J, Palstra R, Klous P, Grosveld F . CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Dev. 2006; 20(17):2349-54. PMC: 1560409. DOI: 10.1101/gad.399506. View