scholarly journals Epigenetic dysregulation from chromosomal transit in micronuclei

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.

scholarly journals A mass spectrometry-based assay using metabolic labeling to rapidly monitor chromatin accessibility of modified histone proteins

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Simone Sidoli ◽  
Mariana Lopes ◽  
Peder J. Lund ◽  
Naomi Goldman ◽  
Maria Fasolino ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Chemical Properties ◽  
Chromatin Accessibility ◽  
Metabolic Labeling ◽  
Post Translational Modifications ◽  
Histone Ptms ◽  
Active Transcription ◽  
Or Gene ◽  
Histone Codes

Abstract Histone post-translational modifications (PTMs) contribute to chromatin accessibility due to their chemical properties and their ability to recruit enzymes responsible for DNA readout and chromatin remodeling. To date, more than 400 different histone PTMs and thousands of combinations of PTMs have been identified, the vast majority with still unknown biological function. Identification and quantification of histone PTMs has become routine in mass spectrometry (MS) but, since raising antibodies for each PTM in a study can be prohibitive, lots of potential is lost from MS datasets when uncharacterized PTMs are found to be significantly regulated. We developed an assay that uses metabolic labeling and MS to associate chromatin accessibility with histone PTMs and their combinations. The labeling is achieved by spiking in the cell media a 5x concentration of stable isotope labeled arginine and allow cells to grow for at least one cell cycle. We quantified the labeling incorporation of about 200 histone peptides with a proteomics workflow, and we confirmed that peptides carrying PTMs with extensively characterized roles in active transcription or gene silencing were in highly or poorly labeled forms, respectively. Data were further validated using next-generation sequencing to assess the transcription rate of chromatin regions modified with five selected PTMs. Furthermore, we quantified the labeling rate of peptides carrying co-existing PTMs, proving that this method is suitable for combinatorial PTMs. We focus on the abundant bivalent mark H3K27me3K36me2, showing that H3K27me3 dominantly represses histone swapping rate even in the presence of the more permissive PTM H3K36me2. Together, we envision this method will help to generate hypotheses regarding histone PTM functions and, potentially, elucidate the role of combinatorial histone codes.

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

2020 ◽  
Author(s):  
Victor Corces ◽  
Yoon Jung ◽  
Brianna Bixler ◽  
Daniel Ruiz ◽  
Hsiao-Lin Wang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Pregnant Mouse ◽  
Chromatin Accessibility ◽  
Epigenetic Alterations ◽  
Transgenerational Inheritance ◽  
Fto Gene ◽  
Intergenic Regions ◽  
F2 Progeny ◽  
Additional Exposure ◽  
F1 Generation

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.

scholarly journals Effects of altering histone post-translational modifications on mitotic chromosome structure and mechanics

2018 ◽  
Author(s):  
Ronald Biggs ◽  
Patrick Liu ◽  
Andrew D. Stephens ◽  
John F. Marko
Keyword(s):  
Large Scale ◽  
Mitotic Chromosome ◽  
Chromosome Doubling ◽  
Chromosome Length ◽  
Force Measurements ◽  
Mitotic Chromosomes ◽  
Post Translational Modifications ◽  
Daughter Cells ◽  
Histone Ptms ◽  
Canonical Histone

AbstractDuring cell division chromatin is compacted into mitotic chromosomes to aid faithful segregation of the genome between two daughter cells. Post-translational modifications (PTM) of histones alter compaction of interphase chromatin, but it remains poorly understood how these modifications affect mitotic chromosome stiffness and structure. Using micropipette-based force measurements and epigenetic drugs, we probed the influence of canonical histone PTMs that dictate interphase euchromatin (acetylation) and heterochromatin (methylation) on mitotic chromosome stiffness. By measuring chromosome doubling force (the force required to double chromosome length), we find that histone methylation, but not acetylation, contributes to mitotic structure and stiffness. We discuss our findings in the context of chromatin gel modeling of the large-scale organization of mitotic chromosomes.

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

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.

Exposure to arsenic and intra-chromosomal instability in blood

Metallomics ◽  
2014 ◽  
Vol 6 (8) ◽  
pp. 1387-1389
Author(s):  
Tomasz K. Wojdacz ◽  
Matteo Bottai ◽  
Marie Vahter ◽  
Karin Broberg
Keyword(s):  
Data Processing ◽  
Copy Number ◽  
Chromosomal Instability ◽  
Processing Algorithm ◽  
Copy Number Alterations ◽  
Data Processing Algorithm ◽  
Infinium Humanmethylation450 Beadchip ◽  
Illumina Infinium Humanmethylation450 Beadchip ◽  
Chip Analysis

The 450k Chip Analysis Methylation Pipeline (ChAMP) is a novel Illumina Infinium HumanMethylation450 BeadChip data processing algorithm that allows the analysis of copy number alterations (CNAs).

scholarly journals Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability

2015 ◽  
Vol 7 (1) ◽  
Author(s):  
Keisuke Toda ◽  
Takeshi Nagasaka ◽  
Yuzo Umeda ◽  
Takehiro Tanaka ◽  
Takashi Kawai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Chromosomal Instability ◽  
Epigenetic Alterations

scholarly journals A G(enomic)P(ositioning)S(ystem) for Plant RNAPII Transcription

2020 ◽  
Author(s):  
Sebastian Marquardt ◽  
Xueyuan Leng ◽  
Quentin Thomas ◽  
Simon Rasmussen
Keyword(s):  
Gene Expression ◽  
Histone Modifications ◽  
Regulation Of Gene Expression ◽  
Positioning System ◽  
Biological Functions ◽  
Post Translational Modifications ◽  
Histone Ptms ◽  
Definition Of ◽  
Generation Sequencing ◽  
Rnapii Transcription

Post-translational modifications (PTMs) of histone residues shape the landscape of gene expression by modulating the dynamic process of RNAPII transcription. The contribution of particular histone modifications to the definition of distinct RNAPII transcription stages remains poorly characterized in plants. Chromatin Immuno-precipitation combined with next-generation sequencing (ChIP-seq) resolves the genomic distribution of histone modifications. Here, we review histone PTM ChIP-seq data in Arabidopsis thaliana and find support for a Genomic Positioning System (GPS) that guides RNAPII transcription. We review the roles of histone PTM “readers”, “writers” and “erasers”, with a focus on the regulation of gene expression and biological functions in plants. The distinct functions of RNAPII transcription during the plant transcription cycle may in part rely on the characteristic histone PTMs profiles that distinguish transcription stages.

scholarly journals Histone modifications during the life cycle of the brown alga Ectocarpus

2020 ◽  
Author(s):  
Simon Bourdareau ◽  
Leila Tirichine ◽  
Bérangère Lombard ◽  
Damarys Loew ◽  
Delphine Scornet ◽  
...  
Keyword(s):  
Life Cycle ◽  
Brown Algae ◽  
Land Plant ◽  
Chromatin Modifications ◽  
Post Translational Modifications ◽  
Transcription Start Sites ◽  
Histone Ptms ◽  
Genomic Regions ◽  
Active Genes

AbstractBackgroundBrown algae evolved complex multicellularity independently of the animal and land plant lineages and are the third most developmentally complex phylogenetic group on the planet. An understanding of developmental processes in this group is expected to provide important insights into the evolutionary events necessary for the emergence of complex multicellularity. Here we have focused on mechanisms of epigenetic regulation involving post-translational modifications (PTMs) of histone proteins.ResultsA total of 47 histone PTMs were identified, including a novel mark H2AZR38me1, but Ectocarpus lacks both H3K27me3 and the major polycomb complexes. ChIP-seq identified PTMs associated with transcription start sites (TSSs) and gene bodies of active genes, and with transposons. H3K79me2 exhibited an unusual pattern, often marking large genomic regions spanning several genes. TSSs of closely spaced divergently transcribed gene pairs shared a common nucleosome depleted region and exhibited shared histone PTM peaks. Overall, patterns of histone PTMs were stable through the life cycle. Analysis of histone PTMs at generation-biased genes identified a correlation between the presence of specific chromatin marks and the level of gene expression.ConclusionsThe overview of histone PTMs in the brown algae presented here will provide a foundation for future studies aimed at understanding the role of chromatin modifications in the regulation of brown algal genomes.

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