Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons

AbstractInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.

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Novel Epigenetic Clock for Fetal Brain Development Predicts Fetal Epigenetic Age for iPSCs and iPSC-Derived Neurons.

10.21203/rs.3.rs-94490/v1 ◽

2020 ◽

Author(s):

Leonard C Steg ◽

Gemma L Shireby ◽

Jennifer Imm ◽

Jonathan P Davies ◽

Robert Flynn ◽

...

Keyword(s):

Dna Methylation ◽

Brain Development ◽

Fetal Brain ◽

Cell Types ◽

Biological Research ◽

Epigenetic Clock ◽

Cellular Model ◽

Neuronal Precursor Cells ◽

Age Related ◽

Epigenetic Age

Abstract Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age, and is has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons, here, we establish the fetal brain clock (FBC), a bespoke epigenetic clock trained in prenatal neurodevelopmental samples. Our data show that the FBC outperforms other established epigenetic clocks in predicting the age of fetal brain samples. We then applied the FBC to DNA methylation data of cellular datasets that have profiled iPSCs and iPSC-derived neuronal precursor cells and neurons and find that these cell types are characterized by a fetal epigenetic age. Furthermore, while differentiation from iPSCs to neurons significantly increases the epigenetic age, iPSC-neurons are still predicted as having fetal epigenetic age. Together our findings reiterate the need for better understanding of the limitations of existing epigenetic clocks for answering biological research questions and highlight a potential limitation of iPSC-neurons as a cellular model for the research of age-related diseases as they might not fully recapitulate an aged phenotype.

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Novel epigenetic clock for fetal brain development predicts fetal epigenetic age for iPSCs and iPSC-derived neurons

10.1101/2020.10.14.339093 ◽

2020 ◽

Author(s):

Leonard C. Steg ◽

Gemma L. Shireby ◽

Jennifer Imm ◽

Jonathan P. Davies ◽

Robert Flynn ◽

...

Keyword(s):

Dna Methylation ◽

Brain Development ◽

Fetal Brain ◽

Cell Types ◽

Biological Research ◽

Epigenetic Clock ◽

Cellular Model ◽

Neuronal Precursor Cells ◽

Age Related ◽

Epigenetic Age

AbstractInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age, and is has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons, here, we establish the fetal brain clock (FBC), a bespoke epigenetic clock trained in prenatal neurodevelopmental samples. Our data show that the FBC outperforms other established epigenetic clocks in predicting the age of fetal brain samples. We then applied the FBC to DNA methylation data of cellular datasets that have profiled iPSCs and iPSC-derived neuronal precursor cells and neurons and find that these cell types are characterized by a fetal epigenetic age. Furthermore, while differentiation from iPSCs to neurons significantly increases the epigenetic age, iPSC-neurons are still predicted as having fetal epigenetic age. Together our findings reiterate the need for better understanding of the limitations of existing epigenetic clocks for answering biological research questions and highlight a potential limitation of iPSC-neurons as a cellular model for the research of age-related diseases as they might not fully recapitulate an aged phenotype.

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DNA methylation on N6-adenine in mammalian embryonic stem cells

Nature ◽

10.1038/nature17640 ◽

2016 ◽

Vol 532 (7599) ◽

pp. 329-333 ◽

Cited By ~ 291

Author(s):

Tao P. Wu ◽

Tao Wang ◽

Matthew G. Seetin ◽

Yongquan Lai ◽

Shijia Zhu ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem

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DAXX safeguards pericentromeric heterochromatin formation in embryonic stem cells

10.1101/2021.04.28.441827 ◽

2021 ◽

Author(s):

Antoine Canat ◽

Adeline Veillet ◽

Robert Illingworth ◽

Emmanuelle Fabre ◽

Pierre Therizols

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Dna Damage ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Pericentric Heterochromatin ◽

Dna Demethylation ◽

Pericentromeric Heterochromatin ◽

Major Satellite ◽

Heterochromatin Formation

AbstractDNA methylation is essential for heterochromatin formation and repression of DNA repeat transcription, both of which are essential for genome integrity. Loss of DNA methylation is associated with disease, including cancer, but is also required for development. Alternative pathways to maintain heterochromatin are thus needed to limit DNA damage accumulation. Here, we find that DAXX, an H3.3 chaperone, protects pericentromeric heterochromatin and is essential for embryonic stem cells (ESCs) maintenance in the ground-state of pluripotency. Upon DNA demethylation-mediated damage, DAXX relocalizes to pericentromeric regions, and recruits PML and SETDB1, thereby promoting heterochromatin formation. In the absence of DAXX, the 3D-architecture and physical properties of pericentric heterochromatin are disrupted, resulting in derepression of major satellite DNA. Using epigenome editing tools, we demonstrate that H3.3, and specifically H3.3K9 modification, directly contribute to maintaining pericentromeric chromatin conformation. Altogether, our data reveal that DAXX and H3.3 unite DNA damage response and heterochromatin maintenance in ESCs.

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Epigenetic clock and DNA methylation studies of roe deer in the wild

10.1101/2020.09.21.306613 ◽

2020 ◽

Author(s):

Jean-François Lemaître ◽

Benjamin Rey ◽

Jean-Michel Gaillard ◽

Corinne Régis ◽

Emmanuelle Gilot ◽

...

Keyword(s):

Dna Methylation ◽

Evolutionary Biology ◽

Roe Deer ◽

Chronological Age ◽

Epigenetic Clock ◽

Aging Effects ◽

Methylation Array ◽

Biomarkers Of Aging ◽

Epigenetic Age ◽

The Relationship

AbstractDNA methylation-based biomarkers of aging (epigenetic clocks) promise to lead to new insights in the evolutionary biology of ageing. Relatively little is known about how the natural environment affects epigenetic aging effects in wild species. In this study, we took advantage of a unique long-term (>40 years) longitudinal monitoring of individual roe deer (Capreolus capreolus) living in two wild populations (Chizé and Trois Fontaines, France) facing different ecological contexts to investigate the relationship between chronological age and levels of DNA methylation (DNAm). We generated novel DNA methylation data from n=90 blood samples using a custom methylation array (HorvathMammalMethylChip40). We present three DNA methylation-based estimators of age (DNAm or epigenetic age), which were trained in males, females, and both sexes combined. We investigated how sex differences influenced the relationship between DNAm age and chronological age through the use of sex-specific epigenetic clocks. Our results highlight that both populations and sex influence the epigenetic age, with the bias toward a stronger male average age acceleration (i.e. differences between epigenetic age and chronological ages) particularly pronounced in the population facing harsh environmental conditions. Further, we identify the main sites of epigenetic alteration that have distinct aging patterns across the two sexes. These findings open the door to promising avenues of research at the crossroad of evolutionary biology and biogerontology.

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Corrigendum: p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

Genes & Development ◽

10.1101/gad.319863.118 ◽

2018 ◽

Vol 32 (19-20) ◽

pp. 1358-1358

Author(s):

Ayala Tovy ◽

Adam Spiro ◽

Ryan McCarthy ◽

Zohar Shipony ◽

Yael Aylon ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Clonal Heterogeneity

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Dysregulation of schizophrenia-associated genes and genome-wide hypomethylation in neurons overexpressing DNMT1

Epigenomics ◽

10.2217/epi-2021-0133 ◽

2021 ◽

Author(s):

Sonal Saxena ◽

Sumana Choudhury ◽

Pranay Amruth Maroju ◽

Anuhya Anne ◽

Lov Kumar ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Copy Number ◽

Embryonic Stem ◽

Wild Type ◽

Independent Manner ◽

Transcript Levels ◽

Genome Wide ◽

Methylation Patterns ◽

Increased Activity

Aim: To study the effects of DNMT1 overexpression on transcript levels of genes dysregulated in schizophrenia and on genome-wide methylation patterns. Materials & methods: Transcriptome and DNA methylome comparisons were made between R1 (wild-type) and Dnmt1tet/tet mouse embryonic stem cells and neurons overexpressing DNMT1. Genes dysregulated in both Dnmt1tet/tet cells and schizophrenia patients were studied further. Results & conclusions: About 50% of dysregulated genes in patients also showed altered transcript levels in Tet/Tet neurons in a DNA methylation-independent manner. These neurons unexpectedly showed genome-wide hypomethylation, increased transcript levels of Tet1 and Apobec 1-3 genes and increased activity and copy number of LINE-1 elements. The observed similarities between Tet/Tet neurons and schizophrenia brain samples reinforce DNMT1 overexpression as a risk factor.

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Effects of a hypomagnetic field on DNA methylation during the differentiation of embryonic stem cells

Scientific Reports ◽

10.1038/s41598-018-37372-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Soonbong Baek ◽

Hwan Choi ◽

Hanseul Park ◽

Byunguk Cho ◽

Siyoung Kim ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Hypomagnetic Field

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Neural Repair in Stroke

Cell Transplantation ◽

10.1177/0963689719863784 ◽

2019 ◽

Vol 28 (9-10) ◽

pp. 1123-1126 ◽

Cited By ~ 4

Author(s):

Nikolas G. Toman ◽

Andrew W. Grande ◽

Walter C. Low

Keyword(s):

Stem Cells ◽

Neural Progenitor Cells ◽

Neuronal Cells ◽

Embryonic Stem ◽

Fetal Brain ◽

Neurological Deficits ◽

Experimental Stroke ◽

Neural Repair ◽

Cell Therapies ◽

Blood Stem Cells

This article reviews the progress that has been made in the development of cell therapies for the repair of nervous system damage caused by strokes, since the first report on the use of cell transplants in animal models of ischemic brain injury in 1988. At that time neural progenitor cells derived from fetal brain tissue were used as sources of cells to replace specific subsets of neuronal cells that were lost in various regions of the brain following experimentally induced strokes. Since 1988, cells from other sources, such as embryonic stem cells and inducible pluripotent stem cells, have been investigated for their ability to replace neuronal cells and repair the damaged brain. Most recently, mesenchymal stem cells and cord blood stem cells have been studied for the ability to modulate the immune system and ameliorate the neuropathology and neurological deficits associated with experimental stroke. The preclinical investigation of different cell therapy approaches for treating stroke during the past three decades has now led to many ongoing clinical trials, with the clinical evaluation of stem cell therapies for stroke now involving global participants.

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