---
_id: '14551'
abstract:
- lang: eng
  text: Methylation of CG dinucleotides (mCGs), which regulates eukaryotic genome
    functions, is epigenetically propagated by Dnmt1/MET1 methyltransferases. How
    mCG is established and transmitted across generations despite imperfect enzyme
    fidelity is unclear. Whether mCG variation in natural populations is governed
    by genetic or epigenetic inheritance also remains mysterious. Here, we show that
    MET1 de novo activity, which is enhanced by existing proximate methylation, seeds
    and stabilizes mCG in Arabidopsis thaliana genes. MET1 activity is restricted
    by active demethylation and suppressed by histone variant H2A.Z, producing localized
    mCG patterns. Based on these observations, we develop a stochastic mathematical
    model that precisely recapitulates mCG inheritance dynamics and predicts intragenic
    mCG patterns and their population-scale variation given only CG site spacing.
    Our results demonstrate that intragenic mCG establishment, inheritance, and variance
    constitute a unified epigenetic process, revealing that intragenic mCG undergoes
    large, millennia-long epigenetic fluctuations and can therefore mediate evolution
    on this timescale.
acknowledgement: We would like to thank Xiaoqi Feng, Ander Movilla Miangolarra, and
  Suzanne de Bruijn for discussions. This work was supported by BBSRC Institute Strategic
  Programme GEN (BB/P013511/1) to M.H. and D.Z. and by a European Research Council
  grant MaintainMeth (725746) to D.Z.
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Amy
  full_name: Briffa, Amy
  last_name: Briffa
- first_name: Elizabeth
  full_name: Hollwey, Elizabeth
  id: b8c4f54b-e484-11eb-8fdc-a54df64ef6dd
  last_name: Hollwey
- first_name: Zaigham
  full_name: Shahzad, Zaigham
  last_name: Shahzad
- first_name: Jonathan D.
  full_name: Moore, Jonathan D.
  last_name: Moore
- first_name: David B.
  full_name: Lyons, David B.
  last_name: Lyons
- first_name: Martin
  full_name: Howard, Martin
  last_name: Howard
- first_name: Daniel
  full_name: Zilberman, Daniel
  id: 6973db13-dd5f-11ea-814e-b3e5455e9ed1
  last_name: Zilberman
  orcid: 0000-0002-0123-8649
citation:
  ama: Briffa A, Hollwey E, Shahzad Z, et al. Millennia-long epigenetic fluctuations
    generate intragenic DNA methylation variance in Arabidopsis populations. <i>Cell
    Systems</i>. 2023;14(11):953-967. doi:<a href="https://doi.org/10.1016/j.cels.2023.10.007">10.1016/j.cels.2023.10.007</a>
  apa: Briffa, A., Hollwey, E., Shahzad, Z., Moore, J. D., Lyons, D. B., Howard, M.,
    &#38; Zilberman, D. (2023). Millennia-long epigenetic fluctuations generate intragenic
    DNA methylation variance in Arabidopsis populations. <i>Cell Systems</i>. Elsevier.
    <a href="https://doi.org/10.1016/j.cels.2023.10.007">https://doi.org/10.1016/j.cels.2023.10.007</a>
  chicago: Briffa, Amy, Elizabeth Hollwey, Zaigham Shahzad, Jonathan D. Moore, David
    B. Lyons, Martin Howard, and Daniel Zilberman. “Millennia-Long Epigenetic Fluctuations
    Generate Intragenic DNA Methylation Variance in Arabidopsis Populations.” <i>Cell
    Systems</i>. Elsevier, 2023. <a href="https://doi.org/10.1016/j.cels.2023.10.007">https://doi.org/10.1016/j.cels.2023.10.007</a>.
  ieee: A. Briffa <i>et al.</i>, “Millennia-long epigenetic fluctuations generate
    intragenic DNA methylation variance in Arabidopsis populations,” <i>Cell Systems</i>,
    vol. 14, no. 11. Elsevier, pp. 953–967, 2023.
  ista: Briffa A, Hollwey E, Shahzad Z, Moore JD, Lyons DB, Howard M, Zilberman D.
    2023. Millennia-long epigenetic fluctuations generate intragenic DNA methylation
    variance in Arabidopsis populations. Cell Systems. 14(11), 953–967.
  mla: Briffa, Amy, et al. “Millennia-Long Epigenetic Fluctuations Generate Intragenic
    DNA Methylation Variance in Arabidopsis Populations.” <i>Cell Systems</i>, vol.
    14, no. 11, Elsevier, 2023, pp. 953–67, doi:<a href="https://doi.org/10.1016/j.cels.2023.10.007">10.1016/j.cels.2023.10.007</a>.
  short: A. Briffa, E. Hollwey, Z. Shahzad, J.D. Moore, D.B. Lyons, M. Howard, D.
    Zilberman, Cell Systems 14 (2023) 953–967.
date_created: 2023-11-19T23:00:54Z
date_published: 2023-11-15T00:00:00Z
date_updated: 2023-11-20T11:24:34Z
day: '15'
ddc:
- '570'
department:
- _id: DaZi
doi: 10.1016/j.cels.2023.10.007
ec_funded: 1
external_id:
  pmid:
  - '37944515'
file:
- access_level: open_access
  checksum: 101fdac59e6f1102d68ef91f2b5bd51a
  content_type: application/pdf
  creator: dernst
  date_created: 2023-11-20T11:22:52Z
  date_updated: 2023-11-20T11:22:52Z
  file_id: '14580'
  file_name: 2023_CellSystems_Briffa.pdf
  file_size: 5587897
  relation: main_file
  success: 1
file_date_updated: 2023-11-20T11:22:52Z
has_accepted_license: '1'
intvolume: '        14'
issue: '11'
language:
- iso: eng
month: '11'
oa: 1
oa_version: Published Version
page: 953-967
pmid: 1
project:
- _id: 62935a00-2b32-11ec-9570-eff30fa39068
  call_identifier: H2020
  grant_number: '725746'
  name: Quantitative analysis of DNA methylation maintenance with chromatin
publication: Cell Systems
publication_identifier:
  eissn:
  - 2405-4720
  issn:
  - 2405-4712
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Millennia-long epigenetic fluctuations generate intragenic DNA methylation
  variance in Arabidopsis populations
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 14
year: '2023'
...
---
_id: '12672'
abstract:
- lang: eng
  text: Cytosine methylation within CG dinucleotides (mCG) can be epigenetically inherited
    over many generations. Such inheritance is thought to be mediated by a semiconservative
    mechanism that produces binary present/absent methylation patterns. However, we
    show here that in Arabidopsis thaliana h1ddm1 mutants, intermediate heterochromatic
    mCG is stably inherited across many generations and is quantitatively associated
    with transposon expression. We develop a mathematical model that estimates the
    rates of semiconservative maintenance failure and de novo methylation at each
    transposon, demonstrating that mCG can be stably inherited at any level via a
    dynamic balance of these activities. We find that DRM2 – the core methyltransferase
    of the RNA-directed DNA methylation pathway – catalyzes most of the heterochromatic
    de novo mCG, with de novo rates orders of magnitude higher than previously thought,
    whereas chromomethylases make smaller contributions. Our results demonstrate that
    stable epigenetic inheritance of mCG in plant heterochromatin is enabled by extensive
    de novo methylation.
acknowledgement: The authors would like to thank Jasper Rine for advice and mentorship
  to D.B.L., Lesley Philips, Timothy Wells, Sophie Able, and Christina Wistrom for
  support with plant growth, and Bhagyshree Jamge and Frédéric Berger for help with
  analysis of ddm1 × WT RNA-sequencing data. This work was supported by BBSRC Institute
  Strategic Program GEN (BB/P013511/1) to X.F., M.H., and D.Z., a European Research
  Council grant MaintainMeth (725746) to D.Z., and a postdoctoral fellowship from
  the Helen Hay Whitney Foundation to D.B.L.
article_number: '112132'
article_processing_charge: Yes
article_type: original
author:
- first_name: David B.
  full_name: Lyons, David B.
  last_name: Lyons
- first_name: Amy
  full_name: Briffa, Amy
  last_name: Briffa
- first_name: Shengbo
  full_name: He, Shengbo
  last_name: He
- first_name: Jaemyung
  full_name: Choi, Jaemyung
  last_name: Choi
- first_name: Elizabeth
  full_name: Hollwey, Elizabeth
  id: b8c4f54b-e484-11eb-8fdc-a54df64ef6dd
  last_name: Hollwey
- first_name: Jack
  full_name: Colicchio, Jack
  last_name: Colicchio
- first_name: Ian
  full_name: Anderson, Ian
  last_name: Anderson
- first_name: Xiaoqi
  full_name: Feng, Xiaoqi
  id: e0164712-22ee-11ed-b12a-d80fcdf35958
  last_name: Feng
  orcid: 0000-0002-4008-1234
- first_name: Martin
  full_name: Howard, Martin
  last_name: Howard
- first_name: Daniel
  full_name: Zilberman, Daniel
  id: 6973db13-dd5f-11ea-814e-b3e5455e9ed1
  last_name: Zilberman
  orcid: 0000-0002-0123-8649
citation:
  ama: Lyons DB, Briffa A, He S, et al. Extensive de novo activity stabilizes epigenetic
    inheritance of CG methylation in Arabidopsis transposons. <i>Cell Reports</i>.
    2023;42(3). doi:<a href="https://doi.org/10.1016/j.celrep.2023.112132">10.1016/j.celrep.2023.112132</a>
  apa: Lyons, D. B., Briffa, A., He, S., Choi, J., Hollwey, E., Colicchio, J., … Zilberman,
    D. (2023). Extensive de novo activity stabilizes epigenetic inheritance of CG
    methylation in Arabidopsis transposons. <i>Cell Reports</i>. Elsevier. <a href="https://doi.org/10.1016/j.celrep.2023.112132">https://doi.org/10.1016/j.celrep.2023.112132</a>
  chicago: Lyons, David B., Amy Briffa, Shengbo He, Jaemyung Choi, Elizabeth Hollwey,
    Jack Colicchio, Ian Anderson, Xiaoqi Feng, Martin Howard, and Daniel Zilberman.
    “Extensive de Novo Activity Stabilizes Epigenetic Inheritance of CG Methylation
    in Arabidopsis Transposons.” <i>Cell Reports</i>. Elsevier, 2023. <a href="https://doi.org/10.1016/j.celrep.2023.112132">https://doi.org/10.1016/j.celrep.2023.112132</a>.
  ieee: D. B. Lyons <i>et al.</i>, “Extensive de novo activity stabilizes epigenetic
    inheritance of CG methylation in Arabidopsis transposons,” <i>Cell Reports</i>,
    vol. 42, no. 3. Elsevier, 2023.
  ista: Lyons DB, Briffa A, He S, Choi J, Hollwey E, Colicchio J, Anderson I, Feng
    X, Howard M, Zilberman D. 2023. Extensive de novo activity stabilizes epigenetic
    inheritance of CG methylation in Arabidopsis transposons. Cell Reports. 42(3),
    112132.
  mla: Lyons, David B., et al. “Extensive de Novo Activity Stabilizes Epigenetic Inheritance
    of CG Methylation in Arabidopsis Transposons.” <i>Cell Reports</i>, vol. 42, no.
    3, 112132, Elsevier, 2023, doi:<a href="https://doi.org/10.1016/j.celrep.2023.112132">10.1016/j.celrep.2023.112132</a>.
  short: D.B. Lyons, A. Briffa, S. He, J. Choi, E. Hollwey, J. Colicchio, I. Anderson,
    X. Feng, M. Howard, D. Zilberman, Cell Reports 42 (2023).
date_created: 2023-02-23T09:17:44Z
date_published: 2023-03-28T00:00:00Z
date_updated: 2023-11-02T12:23:45Z
day: '28'
ddc:
- '580'
department:
- _id: DaZi
- _id: XiFe
doi: 10.1016/j.celrep.2023.112132
ec_funded: 1
external_id:
  isi:
  - '000944921600001'
file:
- access_level: open_access
  checksum: 6cbc44fdb18bf18834c9e2a5b9c67123
  content_type: application/pdf
  creator: kschuh
  date_created: 2023-05-11T10:41:42Z
  date_updated: 2023-05-11T10:41:42Z
  file_id: '12941'
  file_name: 2023_CellReports_Lyons.pdf
  file_size: 8401261
  relation: main_file
  success: 1
file_date_updated: 2023-05-11T10:41:42Z
has_accepted_license: '1'
intvolume: '        42'
isi: 1
issue: '3'
language:
- iso: eng
month: '03'
oa: 1
oa_version: Published Version
project:
- _id: 62935a00-2b32-11ec-9570-eff30fa39068
  call_identifier: H2020
  grant_number: '725746'
  name: Quantitative analysis of DNA methylation maintenance with chromatin
publication: Cell Reports
publication_identifier:
  eissn:
  - 2211-1247
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Extensive de novo activity stabilizes epigenetic inheritance of CG methylation
  in Arabidopsis transposons
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
volume: 42
year: '2023'
...
---
_id: '10533'
abstract:
- lang: eng
  text: Flowering plants utilize small RNA molecules to guide DNA methyltransferases
    to genomic sequences. This RNA-directed DNA methylation (RdDM) pathway preferentially
    targets euchromatic transposable elements. However, RdDM is thought to be recruited
    by methylation of histone H3 at lysine 9 (H3K9me), a hallmark of heterochromatin.
    How RdDM is targeted to euchromatin despite an affinity for H3K9me is unclear.
    Here we show that loss of histone H1 enhances heterochromatic RdDM, preferentially
    at nucleosome linker DNA. Surprisingly, this does not require SHH1, the RdDM component
    that binds H3K9me. Furthermore, H3K9me is dispensable for RdDM, as is CG DNA methylation.
    Instead, we find that non-CG methylation is specifically associated with small
    RNA biogenesis, and without H1 small RNA production quantitatively expands to
    non-CG methylated loci. Our results demonstrate that H1 enforces the separation
    of euchromatic and heterochromatic DNA methylation pathways by excluding the small
    RNA-generating branch of RdDM from non-CG methylated heterochromatin.
acknowledgement: We thank X Feng for helpful comments on the manuscript. This work
  was supported by a European Research Council grant MaintainMeth (725746) to DZ.
article_number: e72676
article_processing_charge: No
article_type: original
author:
- first_name: Jaemyung
  full_name: Choi, Jaemyung
  last_name: Choi
- first_name: David B
  full_name: Lyons, David B
  last_name: Lyons
- first_name: Daniel
  full_name: Zilberman, Daniel
  id: 6973db13-dd5f-11ea-814e-b3e5455e9ed1
  last_name: Zilberman
  orcid: 0000-0002-0123-8649
citation:
  ama: Choi J, Lyons DB, Zilberman D. Histone H1 prevents non-CG methylation-mediated
    small RNA biogenesis in Arabidopsis heterochromatin. <i>eLife</i>. 2021;10. doi:<a
    href="https://doi.org/10.7554/elife.72676">10.7554/elife.72676</a>
  apa: Choi, J., Lyons, D. B., &#38; Zilberman, D. (2021). Histone H1 prevents non-CG
    methylation-mediated small RNA biogenesis in Arabidopsis heterochromatin. <i>ELife</i>.
    eLife Sciences Publications. <a href="https://doi.org/10.7554/elife.72676">https://doi.org/10.7554/elife.72676</a>
  chicago: Choi, Jaemyung, David B Lyons, and Daniel Zilberman. “Histone H1 Prevents
    Non-CG Methylation-Mediated Small RNA Biogenesis in Arabidopsis Heterochromatin.”
    <i>ELife</i>. eLife Sciences Publications, 2021. <a href="https://doi.org/10.7554/elife.72676">https://doi.org/10.7554/elife.72676</a>.
  ieee: J. Choi, D. B. Lyons, and D. Zilberman, “Histone H1 prevents non-CG methylation-mediated
    small RNA biogenesis in Arabidopsis heterochromatin,” <i>eLife</i>, vol. 10. eLife
    Sciences Publications, 2021.
  ista: Choi J, Lyons DB, Zilberman D. 2021. Histone H1 prevents non-CG methylation-mediated
    small RNA biogenesis in Arabidopsis heterochromatin. eLife. 10, e72676.
  mla: Choi, Jaemyung, et al. “Histone H1 Prevents Non-CG Methylation-Mediated Small
    RNA Biogenesis in Arabidopsis Heterochromatin.” <i>ELife</i>, vol. 10, e72676,
    eLife Sciences Publications, 2021, doi:<a href="https://doi.org/10.7554/elife.72676">10.7554/elife.72676</a>.
  short: J. Choi, D.B. Lyons, D. Zilberman, ELife 10 (2021).
date_created: 2021-12-10T13:12:08Z
date_published: 2021-12-01T00:00:00Z
date_updated: 2023-08-17T06:21:08Z
day: '01'
ddc:
- '570'
department:
- _id: DaZi
doi: 10.7554/elife.72676
ec_funded: 1
external_id:
  isi:
  - '000754832000001'
  pmid:
  - '34850679'
file:
- access_level: open_access
  checksum: 22ed4c55fb550f6da02ae55c359be651
  content_type: application/pdf
  creator: dernst
  date_created: 2022-05-16T10:42:22Z
  date_updated: 2022-05-16T10:42:22Z
  file_id: '11384'
  file_name: 2021_eLife_Choi.pdf
  file_size: 2715200
  relation: main_file
  success: 1
file_date_updated: 2022-05-16T10:42:22Z
has_accepted_license: '1'
intvolume: '        10'
isi: 1
keyword:
- genetics and molecular biology
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 62935a00-2b32-11ec-9570-eff30fa39068
  call_identifier: H2020
  grant_number: '725746'
  name: Quantitative analysis of DNA methylation maintenance with chromatin
publication: eLife
publication_identifier:
  issn:
  - 2050-084X
publication_status: published
publisher: eLife Sciences Publications
quality_controlled: '1'
scopus_import: '1'
status: public
title: Histone H1 prevents non-CG methylation-mediated small RNA biogenesis in Arabidopsis
  heterochromatin
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 10
year: '2021'
...