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Epigenetic inheritance is gated by naïve pluripotency and Dppa2

Environmental factors can trigger cellular responses that propagate across mitosis or even generations. Perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. Here, we exp...

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Autores principales: Carlini, Valentina, Policarpi, Cristina, Hackett, Jamie A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982627/
https://www.ncbi.nlm.nih.gov/pubmed/35199868
http://dx.doi.org/10.15252/embj.2021108677
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author Carlini, Valentina
Policarpi, Cristina
Hackett, Jamie A
author_facet Carlini, Valentina
Policarpi, Cristina
Hackett, Jamie A
author_sort Carlini, Valentina
collection PubMed
description Environmental factors can trigger cellular responses that propagate across mitosis or even generations. Perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. Here, we exploit a precision epigenetic editing strategy and forced Xist activity to programme de novo heterochromatin domains (epialleles) at endogenous loci and track their inheritance in a developmental model. We find that naïve pluripotent phases systematically erase ectopic domains of heterochromatin via active mechanisms, which likely acts as an intergenerational safeguard against transmission of epialleles. Upon lineage specification, however, acquired chromatin states can be probabilistically inherited under selectively favourable conditions, including propagation of p53 silencing through in vivo development. Using genome‐wide CRISPR screening, we identify molecular factors that restrict heritable memory of epialleles in naïve pluripotent cells, and demonstrate that removal of chromatin factor Dppa2 unlocks the potential for epigenetic inheritance uncoupled from DNA sequence. Our study outlines a mechanistic basis for how epigenetic inheritance is constrained in mammals, and reveals genomic and developmental contexts in which heritable memory is feasible.
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spelling pubmed-89826272022-04-15 Epigenetic inheritance is gated by naïve pluripotency and Dppa2 Carlini, Valentina Policarpi, Cristina Hackett, Jamie A EMBO J Articles Environmental factors can trigger cellular responses that propagate across mitosis or even generations. Perturbations to the epigenome could underpin such acquired changes, however, the extent and contexts in which modified chromatin states confer heritable memory in mammals is unclear. Here, we exploit a precision epigenetic editing strategy and forced Xist activity to programme de novo heterochromatin domains (epialleles) at endogenous loci and track their inheritance in a developmental model. We find that naïve pluripotent phases systematically erase ectopic domains of heterochromatin via active mechanisms, which likely acts as an intergenerational safeguard against transmission of epialleles. Upon lineage specification, however, acquired chromatin states can be probabilistically inherited under selectively favourable conditions, including propagation of p53 silencing through in vivo development. Using genome‐wide CRISPR screening, we identify molecular factors that restrict heritable memory of epialleles in naïve pluripotent cells, and demonstrate that removal of chromatin factor Dppa2 unlocks the potential for epigenetic inheritance uncoupled from DNA sequence. Our study outlines a mechanistic basis for how epigenetic inheritance is constrained in mammals, and reveals genomic and developmental contexts in which heritable memory is feasible. John Wiley and Sons Inc. 2022-02-24 /pmc/articles/PMC8982627/ /pubmed/35199868 http://dx.doi.org/10.15252/embj.2021108677 Text en ©2022 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Carlini, Valentina
Policarpi, Cristina
Hackett, Jamie A
Epigenetic inheritance is gated by naïve pluripotency and Dppa2
title Epigenetic inheritance is gated by naïve pluripotency and Dppa2
title_full Epigenetic inheritance is gated by naïve pluripotency and Dppa2
title_fullStr Epigenetic inheritance is gated by naïve pluripotency and Dppa2
title_full_unstemmed Epigenetic inheritance is gated by naïve pluripotency and Dppa2
title_short Epigenetic inheritance is gated by naïve pluripotency and Dppa2
title_sort epigenetic inheritance is gated by naïve pluripotency and dppa2
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982627/
https://www.ncbi.nlm.nih.gov/pubmed/35199868
http://dx.doi.org/10.15252/embj.2021108677
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