---
_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: '13965'
abstract:
- lang: eng
  text: Many modes and mechanisms of epigenetic inheritance have been elucidated in
    eukaryotes. Most of them are relatively short-term, generally not exceeding one
    or a few organismal generations. However, emerging evidence indicates that one
    mechanism, cytosine DNA methylation, can mediate epigenetic inheritance over much
    longer timescales, which are mostly or completely inaccessible in the laboratory.
    Here we discuss the evidence for, and mechanisms and implications of, such long-term
    epigenetic inheritance. We argue that compelling evidence supports the long-term
    epigenetic inheritance of gene body methylation, at least in the model angiosperm
    Arabidopsis thaliana, and that variation in such methylation can therefore serve
    as an epigenetic basis for phenotypic variation in natural populations.
article_number: '102087'
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Elizabeth
  full_name: Hollwey, Elizabeth
  id: b8c4f54b-e484-11eb-8fdc-a54df64ef6dd
  last_name: Hollwey
- first_name: Amy
  full_name: Briffa, Amy
  last_name: Briffa
- 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: Hollwey E, Briffa A, Howard M, Zilberman D. Concepts, mechanisms and implications
    of long-term epigenetic inheritance. <i>Current Opinion in Genetics and Development</i>.
    2023;81(8). doi:<a href="https://doi.org/10.1016/j.gde.2023.102087">10.1016/j.gde.2023.102087</a>
  apa: Hollwey, E., Briffa, A., Howard, M., &#38; Zilberman, D. (2023). Concepts,
    mechanisms and implications of long-term epigenetic inheritance. <i>Current Opinion
    in Genetics and Development</i>. Elsevier. <a href="https://doi.org/10.1016/j.gde.2023.102087">https://doi.org/10.1016/j.gde.2023.102087</a>
  chicago: Hollwey, Elizabeth, Amy Briffa, Martin Howard, and Daniel Zilberman. “Concepts,
    Mechanisms and Implications of Long-Term Epigenetic Inheritance.” <i>Current Opinion
    in Genetics and Development</i>. Elsevier, 2023. <a href="https://doi.org/10.1016/j.gde.2023.102087">https://doi.org/10.1016/j.gde.2023.102087</a>.
  ieee: E. Hollwey, A. Briffa, M. Howard, and D. Zilberman, “Concepts, mechanisms
    and implications of long-term epigenetic inheritance,” <i>Current Opinion in Genetics
    and Development</i>, vol. 81, no. 8. Elsevier, 2023.
  ista: Hollwey E, Briffa A, Howard M, Zilberman D. 2023. Concepts, mechanisms and
    implications of long-term epigenetic inheritance. Current Opinion in Genetics
    and Development. 81(8), 102087.
  mla: Hollwey, Elizabeth, et al. “Concepts, Mechanisms and Implications of Long-Term
    Epigenetic Inheritance.” <i>Current Opinion in Genetics and Development</i>, vol.
    81, no. 8, 102087, Elsevier, 2023, doi:<a href="https://doi.org/10.1016/j.gde.2023.102087">10.1016/j.gde.2023.102087</a>.
  short: E. Hollwey, A. Briffa, M. Howard, D. Zilberman, Current Opinion in Genetics
    and Development 81 (2023).
date_created: 2023-08-06T22:01:10Z
date_published: 2023-08-01T00:00:00Z
date_updated: 2023-12-13T12:05:31Z
day: '01'
ddc:
- '570'
department:
- _id: DaZi
doi: 10.1016/j.gde.2023.102087
external_id:
  isi:
  - '001047020200001'
  pmid:
  - '37441873'
file:
- access_level: open_access
  checksum: a294cd9506b80ed6ef218ef44ed32765
  content_type: application/pdf
  creator: dernst
  date_created: 2023-08-07T08:32:26Z
  date_updated: 2023-08-07T08:32:26Z
  file_id: '13980'
  file_name: 2023_CurrentOpinionGenetics_Hollwey.pdf
  file_size: 2568632
  relation: main_file
  success: 1
file_date_updated: 2023-08-07T08:32:26Z
has_accepted_license: '1'
intvolume: '        81'
isi: 1
issue: '8'
language:
- iso: eng
month: '08'
oa: 1
oa_version: Published Version
pmid: 1
publication: Current Opinion in Genetics and Development
publication_identifier:
  eissn:
  - 1879-0380
  issn:
  - 0959-437X
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: Concepts, mechanisms and implications of long-term epigenetic inheritance
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: 81
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'
...