MeCP2 links heterochromatin condensates and neurodevelopmental disease

Charles H. Li; Eliot L. Coffey; Alessandra Dall’Agnese; Nancy M. Hannett; Xin Tang; Jonathan E. Henninger; Jesse M. Platt; Ozgur Oksuz; Alicia V. Zamudio; Lena K. Afeyan; Jurian Schuijers; X. Shawn Liu; Styliani Markoulaki; Tenzin Lungjangwa; Gary LeRoy; Devon S. Svoboda; Emile Wogram; Tong Ihn Lee; Rudolf Jaenisch; Richard A. Young

doi:10.1038/s41586-020-2574-4

MeCP2 links heterochromatin condensates and neurodevelopmental disease

Charles H. Li, Eliot L. Coffey, Alessandra Dall’Agnese, Nancy M. Hannett, Xin Tang, Jonathan E. Henninger, Jesse M. Platt, Ozgur Oksuz, Alicia V. Zamudio, Lena K. Afeyan, Jurian Schuijers, X. Shawn Liu, Styliani Markoulaki, Tenzin Lungjangwa, Gary LeRoy, Devon S. Svoboda, Emile Wogram, Tong Ihn Lee, Rudolf Jaenisch^*, Richard A. Young

^*Corresponding author for this work

Cell & Developmental Biology

Research output: Contribution to journal › Article › peer-review

115 Scopus citations

Abstract

Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing^1–3. Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome^3–5, which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure^1,2, heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate^6,7. Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome.

Original language	English (US)
Pages (from-to)	440-444
Number of pages	5
Journal	Nature
Volume	586
Issue number	7829
DOIs	https://doi.org/10.1038/s41586-020-2574-4
State	Published - Oct 15 2020

Funding

Acknowledgements We thank A. P. Bird for sharing Mecp2 mutant cell lines; D. Reinberg for sharing purified poly-nucleosomes; P. A. Sharp for discussions; D. Richardson and the Harvard Center for Biological Imaging; W. Salmon and the Whitehead W.M. Keck Microscopy Facility; and R. Flannery, J. Drotar, N. Rosenau and the Whitehead Genetically Engineered Models Center for technical support. The work was supported by NIH grant R01 GM123511 (R.A.Y.), NSF grant PHY1743900 (R.A.Y.), NIH grant 2 R01 MH104610-20 (R.J., R.A.Y.), NIH grant R37 CA084198 (R.J.), Hope Funds for Cancer Research Fellowship (A.D.), NIH grant T32 5T32DK007191-45 (J.M.P.), NSF Graduate Research Fellowship (A.V.Z.), and NIH grant K99/R00 MH113813 (X.S.L.). MECP2 gene expression values in transcripts per million (TPM) from RNA-seq of human tissues were acquired from the Genotype-Tissue Expression (GTEx) project release v.7. In instances where multiple regions of the same tissue were assayed, the highest expression value was used to represent the tissue. TPM values greater than 1 were considered to be expressed. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS.

ASJC Scopus subject areas

General

Access to Document

10.1038/s41586-020-2574-4

Cite this

Li, C. H., Coffey, E. L., Dall’Agnese, A., Hannett, N. M., Tang, X., Henninger, J. E., Platt, J. M., Oksuz, O., Zamudio, A. V., Afeyan, L. K., Schuijers, J., Liu, X. S., Markoulaki, S., Lungjangwa, T., LeRoy, G., Svoboda, D. S., Wogram, E., Lee, T. I., Jaenisch, R., & Young, R. A. (2020). MeCP2 links heterochromatin condensates and neurodevelopmental disease. Nature, 586(7829), 440-444. https://doi.org/10.1038/s41586-020-2574-4

@article{44a29f018725439c9409f9cfc5a6c4a8,

title = "MeCP2 links heterochromatin condensates and neurodevelopmental disease",

abstract = "Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing1–3. Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome3–5, which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure1,2, heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate6,7. Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome.",

author = "Li, {Charles H.} and Coffey, {Eliot L.} and Alessandra Dall{\textquoteright}Agnese and Hannett, {Nancy M.} and Xin Tang and Henninger, {Jonathan E.} and Platt, {Jesse M.} and Ozgur Oksuz and Zamudio, {Alicia V.} and Afeyan, {Lena K.} and Jurian Schuijers and Liu, {X. Shawn} and Styliani Markoulaki and Tenzin Lungjangwa and Gary LeRoy and Svoboda, {Devon S.} and Emile Wogram and Lee, {Tong Ihn} and Rudolf Jaenisch and Young, {Richard A.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = oct,

day = "15",

doi = "10.1038/s41586-020-2574-4",

language = "English (US)",

volume = "586",

pages = "440--444",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7829",

}

Li, CH, Coffey, EL, Dall’Agnese, A, Hannett, NM, Tang, X, Henninger, JE, Platt, JM, Oksuz, O, Zamudio, AV, Afeyan, LK, Schuijers, J, Liu, XS, Markoulaki, S, Lungjangwa, T, LeRoy, G, Svoboda, DS, Wogram, E, Lee, TI, Jaenisch, R & Young, RA 2020, 'MeCP2 links heterochromatin condensates and neurodevelopmental disease', Nature, vol. 586, no. 7829, pp. 440-444. https://doi.org/10.1038/s41586-020-2574-4

TY - JOUR

T1 - MeCP2 links heterochromatin condensates and neurodevelopmental disease

AU - Li, Charles H.

AU - Coffey, Eliot L.

AU - Dall’Agnese, Alessandra

AU - Hannett, Nancy M.

AU - Tang, Xin

AU - Henninger, Jonathan E.

AU - Platt, Jesse M.

AU - Oksuz, Ozgur

AU - Zamudio, Alicia V.

AU - Afeyan, Lena K.

AU - Schuijers, Jurian

AU - Liu, X. Shawn

AU - Markoulaki, Styliani

AU - Lungjangwa, Tenzin

AU - LeRoy, Gary

AU - Svoboda, Devon S.

AU - Wogram, Emile

AU - Lee, Tong Ihn

AU - Jaenisch, Rudolf

AU - Young, Richard A.

PY - 2020/10/15

Y1 - 2020/10/15

N2 - Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing1–3. Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome3–5, which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure1,2, heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate6,7. Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome.

AB - Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing1–3. Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome3–5, which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure1,2, heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate6,7. Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome.

UR - http://www.scopus.com/inward/record.url?scp=85087965884&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85087965884&partnerID=8YFLogxK

U2 - 10.1038/s41586-020-2574-4

DO - 10.1038/s41586-020-2574-4

M3 - Article

C2 - 32698189

AN - SCOPUS:85087965884

SN - 0028-0836

VL - 586

SP - 440

EP - 444

JO - Nature

JF - Nature

IS - 7829

ER -

MeCP2 links heterochromatin condensates and neurodevelopmental disease

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this