---
_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
license: https://creativecommons.org/licenses/by/4.0/
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: '11449'
abstract:
- lang: eng
  text: Mutations are acquired frequently, such that each cell's genome inscribes
    its history of cell divisions. Common genomic alterations involve loss of heterozygosity
    (LOH). LOH accumulates throughout the genome, offering large encoding capacity
    for inferring cell lineage. Using only single-cell RNA sequencing (scRNA-seq)
    of mouse brain cells, we found that LOH events spanning multiple genes are revealed
    as tracts of monoallelically expressed, constitutionally heterozygous single-nucleotide
    variants (SNVs). We simultaneously inferred cell lineage and marked developmental
    time points based on X chromosome inactivation and the total number of LOH events
    while identifying cell types from gene expression patterns. Our results are consistent
    with progenitor cells giving rise to multiple cortical cell types through stereotyped
    expansion and distinct waves of neurogenesis. This type of retrospective analysis
    could be incorporated into scRNA-seq pipelines and, compared with experimental
    approaches for determining lineage in model organisms, is applicable where genetic
    engineering is prohibited, such as humans.
acknowledgement: D.J.A. thanks Wayne K. Potts, Alan R. Rogers, Kristen Hawkes, Ryk
  Ward, and Jon Seger for inspiring a young undergraduate to apply evolutionary theory
  to intraorganism development. Supported by the Paul G. Allen Frontiers Group (University
  of Washington); NIH R00HG010152 (Dartmouth); and NÖ Forschung und Bildung n[f+b]
  life science call grant (C13-002) and the European Research Council (ERC) under
  the European Union’s Horizon 2020 research and innovation program 725780 LinPro
  to S.H.
article_processing_charge: No
article_type: original
author:
- first_name: Donovan J.
  full_name: Anderson, Donovan J.
  last_name: Anderson
- first_name: Florian
  full_name: Pauler, Florian
  id: 48EA0138-F248-11E8-B48F-1D18A9856A87
  last_name: Pauler
- first_name: Aaron
  full_name: Mckenna, Aaron
  last_name: Mckenna
- first_name: Jay
  full_name: Shendure, Jay
  last_name: Shendure
- first_name: Simon
  full_name: Hippenmeyer, Simon
  id: 37B36620-F248-11E8-B48F-1D18A9856A87
  last_name: Hippenmeyer
  orcid: 0000-0003-2279-1061
- first_name: Marshall S.
  full_name: Horwitz, Marshall S.
  last_name: Horwitz
citation:
  ama: Anderson DJ, Pauler F, Mckenna A, Shendure J, Hippenmeyer S, Horwitz MS. Simultaneous
    brain cell type and lineage determined by scRNA-seq reveals stereotyped cortical
    development. <i>Cell Systems</i>. 2022;13(6):438-453.e5. doi:<a href="https://doi.org/10.1016/j.cels.2022.03.006">10.1016/j.cels.2022.03.006</a>
  apa: Anderson, D. J., Pauler, F., Mckenna, A., Shendure, J., Hippenmeyer, S., &#38;
    Horwitz, M. S. (2022). Simultaneous brain cell type and lineage determined by
    scRNA-seq reveals stereotyped cortical development. <i>Cell Systems</i>. Elsevier.
    <a href="https://doi.org/10.1016/j.cels.2022.03.006">https://doi.org/10.1016/j.cels.2022.03.006</a>
  chicago: Anderson, Donovan J., Florian Pauler, Aaron Mckenna, Jay Shendure, Simon
    Hippenmeyer, and Marshall S. Horwitz. “Simultaneous Brain Cell Type and Lineage
    Determined by ScRNA-Seq Reveals Stereotyped Cortical Development.” <i>Cell Systems</i>.
    Elsevier, 2022. <a href="https://doi.org/10.1016/j.cels.2022.03.006">https://doi.org/10.1016/j.cels.2022.03.006</a>.
  ieee: D. J. Anderson, F. Pauler, A. Mckenna, J. Shendure, S. Hippenmeyer, and M.
    S. Horwitz, “Simultaneous brain cell type and lineage determined by scRNA-seq
    reveals stereotyped cortical development,” <i>Cell Systems</i>, vol. 13, no. 6.
    Elsevier, p. 438–453.e5, 2022.
  ista: Anderson DJ, Pauler F, Mckenna A, Shendure J, Hippenmeyer S, Horwitz MS. 2022.
    Simultaneous brain cell type and lineage determined by scRNA-seq reveals stereotyped
    cortical development. Cell Systems. 13(6), 438–453.e5.
  mla: Anderson, Donovan J., et al. “Simultaneous Brain Cell Type and Lineage Determined
    by ScRNA-Seq Reveals Stereotyped Cortical Development.” <i>Cell Systems</i>, vol.
    13, no. 6, Elsevier, 2022, p. 438–453.e5, doi:<a href="https://doi.org/10.1016/j.cels.2022.03.006">10.1016/j.cels.2022.03.006</a>.
  short: D.J. Anderson, F. Pauler, A. Mckenna, J. Shendure, S. Hippenmeyer, M.S. Horwitz,
    Cell Systems 13 (2022) 438–453.e5.
date_created: 2022-06-19T22:01:57Z
date_published: 2022-06-15T00:00:00Z
date_updated: 2023-08-03T07:19:43Z
day: '15'
department:
- _id: SiHi
doi: 10.1016/j.cels.2022.03.006
ec_funded: 1
external_id:
  isi:
  - '000814124400002'
  pmid:
  - '35452605'
intvolume: '        13'
isi: 1
issue: '6'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1016/j.cels.2022.03.006
month: '06'
oa: 1
oa_version: Published Version
page: 438-453.e5
pmid: 1
project:
- _id: 260018B0-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '725780'
  name: Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development
- _id: 25D92700-B435-11E9-9278-68D0E5697425
  grant_number: LS13-002
  name: Mapping Cell-Type Specificity of the Genomic Imprintome in the Brain
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: Simultaneous brain cell type and lineage determined by scRNA-seq reveals stereotyped
  cortical development
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 13
year: '2022'
...