Transgenerational inheritance of BPA-induced obesity correlates with transmission of new CTCF sites in the Fto gene

Abstract The mechanisms by which epiphenotypes are transmitted transgenerationally through the parental germlines are poorly understood. Here we show that exposure of pregnant mouse F0 females during E7.5-E13.5 to bisphenol A results in obesity in the F2 progeny in the absence of additional exposure. This epiphenotype can be transmitted through the male and female germlines up to the F5 generation, decreases in F6, and disappears in F7. Analyses of chromatin changes in the sperm of the F1 generation reveal a widespread increase in chromatin accessibility at binding sites for CTCF and other transcription factors accompanied by alterations in 3D organization. Comparison of the transmission of obesity between F2 and F5 and its disappearance in F7 with alterations in the binding of these transcription factors points to the activation of two enhancers located in intronic and intergenic regions of the Fto gene as the cause of transgenerational inheritance. These enhancers form an autoregulatory feedback loop that, in combination with a decrease of m6A in sperm RNAs, may cause alterations of gene expression in the embryo after fertilization. Given the established involvement of SNPs in FTO in human obesity, the results suggest that both genetic and epigenetic alterations of the same gene can lead to the same phenotypic outcomes on human health.

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Transgenerational inheritance of BPA-induced obesity correlates with transmission of new CTCF sites in the Fto gene

10.1101/2020.11.20.391672 ◽

2020 ◽

Author(s):

Yoon Hee Jung ◽

Brianna J. Bixler ◽

Daniel Ruiz ◽

Hsiao-Lin V. Wang ◽

Hannah Linsenbaum ◽

...

Keyword(s):

Transcription Factors ◽

Binding Sites ◽

Pregnant Mouse ◽

Chromatin Accessibility ◽

Epigenetic Alterations ◽

Transgenerational Inheritance ◽

Fto Gene ◽

F2 Progeny ◽

Additional Exposure ◽

F1 Generation

AbstractThe mechanisms by which epiphenotypes are transmitted transgenerationally through the parental germlines are poorly understood. Here we show that exposure of pregnant mouse F0 females during E7.5-E13.5 to bisphenol A results in obesity in the F2 progeny in the absence of additional exposure. This epiphenotype can be transmitted through the male and female germlines up to the F5 generation, decreases in F6, and disappears in F7. Analysis of chromatin changes in the sperm of the F1 generation reveals a widespread increase in chromatin accessibility at binding sites for CTCF and other transcription factors accompanied by alterations in 3D organization. Comparison of the transmission of obesity between F2 and F5 and its disappearance in F7 with alterations in the binding of these transcription factors points to the activation of an enhancer in an intron of the Fto gene as the cause of transgenerational inheritance. Activation of the Fto enhancer results in a decrease of m6A in sperm RNAs, which may result in alterations of gene expression in the embryo after fertilization. Given the established involvement of SNPs in FTO in human obesity, the results suggest that both genetic and epigenetic alterations of the same gene can lead to the same phenotypic outcomes on human health.

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Integration of sperm ncRNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance

Epigenetics & Chromatin ◽

10.1186/s13072-020-00378-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Daniel Beck ◽

Millissia Ben Maamar ◽

Michael K. Skinner

Keyword(s):

Dna Methylation ◽

Potential Role ◽

Epigenetic Alterations ◽

Adult Males ◽

Transgenerational Inheritance ◽

Non Coding Rna ◽

F2 Generation ◽

Genetic Form ◽

F1 Generation ◽

Epigenetic Processes

Abstract Background Environmentally induced epigenetic transgenerational inheritance of pathology and phenotypic variation has been demonstrated in all organisms investigated from plants to humans. This non-genetic form of inheritance is mediated through epigenetic alterations in the sperm and/or egg to subsequent generations. Although the combined regulation of differential DNA methylated regions (DMR), non-coding RNA (ncRNA), and differential histone retention (DHR) have been shown to occur, the integration of these different epigenetic processes remains to be elucidated. The current study was designed to examine the integration of the different epigenetic processes. Results A rat model of transiently exposed F0 generation gestating females to the agricultural fungicide vinclozolin or pesticide DDT (dichloro-diphenyl-trichloroethane) was used to acquire the sperm from adult males in the subsequent F1 generation offspring, F2 generation grand offspring, and F3 generation great-grand offspring. The F1 generation sperm ncRNA had substantial overlap with the F1, F2 and F3 generation DMRs, suggesting a potential role for RNA-directed DNA methylation. The DMRs also had significant overlap with the DHRs, suggesting potential DNA methylation-directed histone retention. In addition, a high percentage of DMRs induced in the F1 generation sperm were maintained in subsequent generations. Conclusions Many of the DMRs, ncRNA, and DHRs were colocalized to the same chromosomal location regions. Observations suggest an integration of DMRs, ncRNA, and DHRs in part involve RNA-directed DNA methylation and DNA methylation-directed histone retention in epigenetic transgenerational inheritance.

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ATF3 drives senescence by reconstructing accessible chromatin profiles

10.1101/2020.08.13.249458 ◽

2020 ◽

Author(s):

Chao Zhang ◽

Xuebin Zhang ◽

Yiting Guan ◽

Xiaoke Huang ◽

Lijun Zhang ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Transcription Factors ◽

Regulatory Mechanism ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Dynamic Landscape ◽

Intergenic Regions ◽

Senescence Program ◽

Accessible Chromatin

AbstractChromatin architecture and gene expression profile undergo tremendous reestablishment during senescence. However, the regulatory mechanism between chromatin reconstruction and gene expression in senescence remain elusive. The chromatin accessibility is an excellent perspective to reveal the latent regulatory elements. Thus, we depicted the landscapes of chromatin accessibility and gene expression during HUVECs senescence. We found that chromatin accessibilities are re-distributed during senescence. The senescence related increased accessible regions (IARs) and the decreased accessible regions (DARs) are mainly distributed in distal intergenic regions. The DARs are correlated with the function declines caused by senescence, whereas the IARs are involved in the regulation for senescence program. Moreover, the heterochromatin contributes most of IARs in senescent cells. We identified that the AP-1 transcription factors, especially ATF3 is responsible for driving chromatin accessibility reconstruction in IARs. In particular, DNA methylation is negatively correlated with chromatin accessibility during senescence. AP-1 motifs with low DNA methylation may improve their binding affinity in IARs and further opens the chromatin nearby. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program. And we identified a cellular senescence regulator, AP-1, which promotes senescence through organizing the accessibility profile in IARs.

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Epigenetic dysregulation from chromosomal transit in micronuclei

10.1101/2022.01.12.475944 ◽

2022 ◽

Author(s):

Albert Agustinus ◽

Ramya Raviram ◽

Bhargavi Dameracharla ◽

Jens Luebeck ◽

Stephanie Stransky ◽

...

Keyword(s):

Chromosomal Instability ◽

Chromatin Accessibility ◽

Epigenetic Alterations ◽

Copy Number Alterations ◽

Mitotic Chromosomes ◽

Post Translational Modifications ◽

Positional Bias ◽

Histone Ptms ◽

Mitotic Abnormalities ◽

Intergenic Regions

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers [1-4], yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei [5, 6], and subsequent micronuclear envelope rupture [7] profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and non-transformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer.

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Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis

PLoS ONE ◽

10.1371/journal.pone.0170859 ◽

2017 ◽

Vol 12 (1) ◽

pp. e0170859 ◽

Cited By ~ 22

Author(s):

Iveta Yotova ◽

Emily Hsu ◽

Catherine Do ◽

Aulona Gaba ◽

Matthias Sczabolcs ◽

...

Keyword(s):

Transcription Factors ◽

Signaling Pathways ◽

Stromal Cells ◽

Epigenetic Alterations

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ASC proneural transcription factors mediate the timely initiation of the neural program during neuroectodermal to neuroblast transition ensuring progeny fidelity

10.1101/2021.11.02.466869 ◽

2021 ◽

Author(s):

Vasiliki Theodorou ◽

Aikaterini Stefanaki ◽

Minas Drakos ◽

Dafne Triantafyllou ◽

Christos Delidakis

Keyword(s):

Transcription Factors ◽

Target Genes ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Cis Elements ◽

Enhancer Activity ◽

Timely Initiation ◽

Chromatin Dynamics ◽

Neural Fate ◽

Neural Specification

Background: ASC/ASCL proneural transcription factors are oncogenic and exhibit impressive reprogramming and pioneer activities. In both Drosophila and mammals, these factors are central in the early specification of the neural fate, where they act in opposition to Notch signalling. However, the role of ASC on the chromatin during CNS neural stem cells birth remains elusive. Results: We investigated the chromatin changes accompanying neural commitment using an integrative genetics and genomics methodology. We found that ASC factors bind equally strongly to two distinct classes of cis-regulatory elements: open regions remodeled earlier during maternal to zygotic transition by Zelda and Zelda-independent, less accessible regions. Both classes cis-elements exhibit enhanced chromatin accessibility during neural specification and correlate with transcriptional regulation of genes involved in many biological processes necessary for neuroblast function. We identified an ASC-Notch regulated TF network that most likely act as the prime regulators of neuroblast function. Using a cohort of ASC target genes, we report that ASC null neuroblasts are defectively specified, remaining initially stalled, lacking expression of many proneural targets and unable to divide. When they eventually start proliferating, they produce compromised progeny. Generation of lacZ reporter lines driven by proneural-bound elements display enhancer activity within neuroblasts and proneural dependency. Therefore, the partial neuroblast identity seen in the absence of ASC genes is driven by other, proneural-independent, cis-elements. Neuroblast impairment and the late differentiation defects of ASC mutants are corrected by ectodermal induction of individual ASC genes but not by individual members of the TF network downstream of ASC. However, in wild type embryos induction of individual members of this network induces CNS hyperplasia, suggesting that they synergize with the activating function of ASC to establish the chromatin dynamics that promote neural specification. Conclusion: ASC factors bind a large number of enhancers to orchestrate the timely activation of the neural chromatin program during neuroectodermal to neuroblast transition. This early chromatin remodeling is crucial for both neuroblast homeostasis as well as future progeny fidelity.

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Abstract P493: Histone Reader PHF7 Cooperates With The SWI/SNF Complex At Cardiac Super Enhancers To Promote Direct Reprogramming

Circulation Research ◽

10.1161/res.129.suppl_1.p493 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Glynnis A Garry ◽

Svetlana Bezprozvannaya ◽

Huanyu Zhou ◽

Hisayuki Hashimoto ◽

Kenian Chen ◽

...

Keyword(s):

Transcription Factors ◽

Cardiac Fibroblasts ◽

Human Fibroblasts ◽

Cell Types ◽

Chromatin Accessibility ◽

Direct Reprogramming ◽

Ischemic Disease ◽

Treat Heart Failure ◽

Cardiac Transcription Factors ◽

Adult Fibroblasts

Ischemic heart disease is the leading cause of death worldwide. Direct reprogramming of resident cardiac fibroblasts (CFs) to induced cardiomyocytes (iCLMs) has emerged as a potential therapeutic approach to treat heart failure and ischemic disease. Cardiac reprogramming was first achieved through forced expression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT); our laboratory found that Hand2 (GHMT) and Akt1 (AGHMT) markedly enhanced reprogramming efficiency in embryonic and postnatal cell types. However, adult mouse and human fibroblasts are resistant to reprogramming due to staunch epigenetic barriers. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the epigenetic reader PHF7 as the most potent activating factor. We validated the findings of this screen and found that PHF7 augmented reprogramming of adult fibroblasts ten-fold. Mechanistically, PHF7 localized to cardiac super enhancers in fibroblasts by reading H3K4me2 marks, and through cooperation with the SWI/SNF complex, increased chromatin accessibility and transcription factor binding at these multivalent enhancers. Further, PHF7 recruited cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. Importantly, PHF7 achieved efficient reprogramming through these mechanisms in the absence of Gata4. Collectively, these studies highlight the underexplored necessity of cardiac epigenetic readers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

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Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2

Nucleic Acids Research ◽

10.1093/nar/gkz627 ◽

2019 ◽

Vol 47 (17) ◽

pp. 9069-9086 ◽

Cited By ~ 10

Author(s):

Filippo M Cernilogar ◽

Stefan Hasenöder ◽

Zeyang Wang ◽

Katharina Scheibner ◽

Ingo Burtscher ◽

...

Keyword(s):

Transcription Factors ◽

Binding Sites ◽

Specific Binding ◽

Embryonic Stem ◽

Chromatin Accessibility ◽

Specific Binding Sites ◽

Nucleosomal Dna ◽

Cell Type Specific ◽

Chromatin Opening ◽

Selection Of

Abstract Pioneer transcription factors (PTF) can recognize their binding sites on nucleosomal DNA and trigger chromatin opening for recruitment of other non-pioneer transcription factors. However, critical properties of PTFs are still poorly understood, such as how these transcription factors selectively recognize cell type-specific binding sites and under which conditions they can initiate chromatin remodelling. Here we show that early endoderm binding sites of the paradigm PTF Foxa2 are epigenetically primed by low levels of active chromatin modifications in embryonic stem cells (ESC). Priming of these binding sites is supported by preferential recruitment of Foxa2 to endoderm binding sites compared to lineage-inappropriate binding sites, when ectopically expressed in ESCs. We further show that binding of Foxa2 is required for chromatin opening during endoderm differentiation. However, increased chromatin accessibility was only detected on binding sites which are synergistically bound with other endoderm transcription factors. Thus, our data suggest that binding site selection of PTFs is directed by the chromatin environment and that chromatin opening requires collaboration of PTFs with additional transcription factors.

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Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations during Mammalian Development

Cells ◽

10.3390/cells8121559 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1559 ◽

Cited By ~ 7

Author(s):

Louis Legoff ◽

Shereen Cynthia D’Cruz ◽

Sergei Tevosian ◽

Michael Primig ◽

Fatima Smagulova

Keyword(s):

Molecular Mechanisms ◽

Disease Risk ◽

Current Knowledge ◽

Epigenetic Inheritance ◽

Epigenetic Alterations ◽

Transgenerational Inheritance ◽

Mammalian Development ◽

Genetic Studies ◽

Salient Points ◽

Chromatin Proteins

Genetic studies traditionally focus on DNA as the molecule that passes information on from parents to their offspring. Changes in the DNA code alter heritable information and can more or less severely affect the progeny’s phenotype. While the idea that information can be inherited between generations independently of the DNA’s nucleotide sequence is not new, the outcome of recent studies provides a mechanistic foundation for the concept. In this review, we attempt to summarize our current knowledge about the transgenerational inheritance of environmentally induced epigenetic changes. We focus primarily on studies using mice but refer to other species to illustrate salient points. Some studies support the notion that there is a somatic component within the phenomenon of epigenetic inheritance. However, here, we will mostly focus on gamete-based processes and the primary molecular mechanisms that are thought to contribute to epigenetic inheritance: DNA methylation, histone modifications, and non-coding RNAs. Most of the rodent studies published in the literature suggest that transgenerational epigenetic inheritance through gametes can be modulated by environmental factors. Modification and redistribution of chromatin proteins in gametes is one of the major routes for transmitting epigenetic information from parents to the offspring. Our recent studies provide additional specific cues for this concept and help better understand environmental exposure influences fitness and fidelity in the germline. In summary, environmental cues can induce parental alterations and affect the phenotypes of offspring through gametic epigenetic inheritance. Consequently, epigenetic factors and their heritability should be considered during disease risk assessment.

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Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone

Nature Communications ◽

10.1038/s41467-020-18955-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Pavlo Lutsik ◽

Annika Baude ◽

Daniela Mancarella ◽

Simin Öz ◽

Alexander Kühn ◽

...

Keyword(s):

Dna Methylation ◽

Osteogenic Differentiation ◽

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Chromatin Accessibility ◽

Cell Tumor ◽

Epigenetic Alterations ◽

Epigenetic Landscape ◽

Line System

Abstract The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.

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