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Point cloud characterization
Published in Rodrigo Rojas Moraleda, Nektarios A. Valous, Wei Xiong, Niels Halama, Computational Topology for Biomedical Image and Data Analysis, 2019
Rodrigo Rojas Moraleda, Nektarios A. Valous, Wei Xiong, Niels Halama
A dataset consisting of 360 SPDM images as point clouds is used for validation. Green and yellow fluorescent protein markers are used for labelling chromatin. Antibodies for the histones H3K4 and H4K20 are used to label euchromatin and heterochromatin, respectively. The results show that heterochromatic regions alone indicate a relaxation after radiation exposure and re-condensation during repair, while euchromatin seems to be unaffected or behaves in a contrary fashion (Fig. 5.1ii). This differentiation can be seen by the respective persistent diagrams (Fig. 5.1i).
Developmental plasticity, epigenetic mechanisms and early life influences on adult health and disease: Fundamental concepts
Published in Nicholas C. Harvey, Cyrus Cooper, Osteoporosis: a lifecourse epidemiology approach to skeletal health, 2018
Elizabeth M Curtis, Karen Lillycrop, Mark Hanson
Post-translational histone modifications and the accompanying histone-modifying enzymes form a major part of the epigenetic regulation of genes. DNA is wrapped around an octamer of four different histone molecules (H2A, H2B, H3 and H4) to form a nucleosome, the basic unit of chromatin. The flexible N-terminal tails of core histones that protrude from the nucleosome undergo various post-translational modifications, including acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP ribosylation, deamination and noncovalent proline isomerization (21). The patterns of histone modifications alter the transcriptional accessibility of the chromatin. It has been shown that euchromatin, a more relaxed, actively transcribed state of DNA, is characterized by high levels of acetylation and trimethylated (H3) lysine residues (K-number) on specific histones H3K4, H3K36 and H3K79, while low levels of acetylation and high levels of H3K9, H3K27 and H4K20 methylation are indicative of a more condensed, transcriptionally inactive heterochromatin (22). The majority of histone post-translational modifications are dynamic and regulated by families of enzymes that promote or reverse specific modifications, such as histone acetyltransferases (HATs), which add acetylation marks, whereas histone deacetylases (HDACs) remove them. Many transcriptional co-activators or co-repressors possess either HAT or HDAC activity or associate with these enzymes, so the balance between histone methylation and acetylation and demethylation/deacetylation is important in modifying expression of target genes.
Epigenetics of exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Daniel C. Turner, Robert A. Seaborne, Adam P. Sharples
Diverting our attention towards histone methylation, Ohsawa et al. also looked at the methylation levels of different histone proteins across the different training regimes. The authors specifically focussed on the tri-methylation of histone 4 on lysine 20 (H4K20me3) as this particular modification is associated with ‘condensed’ chromatin (i.e. heterochromatin) and therefore reduced gene expression (74). Interestingly, in the regime that demonstrated increased total levels of H3.3 described above, the levels of H4K20me3 significantly decreased (71). These findings may therefore suggest that the endurance exercise-induced increase in the total level of H3.3 variants was able to mitigate the condensed chromatin state typically induced by the tri-methylation of H4K20 that would otherwise result in reduced gene expression (71). In contrast to the inhibitory effects of methylated H4K20 on gene transcription, methylation of other histone proteins (particularly histone 3) is oppositely associated with increased gene transcription, such as tri-methylation of lysine 4 on histone 3 (H3K4). Therefore, this modification has attracted the attention of researchers to study this mark in the context of exercise. In one study, also described earlier in this chapter, mice that performed progressive endurance exercise did not demonstrate reduced DNA methylation levels of the PGC-1α alternative B promoter, rather, the authors reported an increase in H3K4me3 methylation that corresponded to a large increase in PGC-1α alternative B promoter gene expression (45). Given that the authors also observed hypomethylation of DNA in PGC-1α’s canonical promoter A after exercise (that did not affect gene expression) whereas increased H3K4me3 of PGC-1α’s alternative promoter B corresponded with increased gene expression, collectively indicates that histone methylation (together with H3K27 acetylation (46)) maybe key epigenetic modifications underpinning increased PGC-1α gene expression following endurance exercise. However, contrasting results that identified associated promoter DNA hypomethylation and increased gene expression of PGC-1α after endurance exercise in humans (43) make it difficult to generalise these finding across species.
Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals
Published in The World Journal of Biological Psychiatry, 2019
Dimitry A. Chistiakov, Vladimir P. Chekhonin
Two families of histone lysine demethylases are involved in lysine demethylation. For oxidative demethylation, the first family (KDM) employs the amine oxidase domain, while the second class (JMJD) uses the jumonji domain. JMJD demethylases belong to Fe2+- and 2-oxoglutarate-dependent oxygenases (Dimitrova et al. 2015). Methylation of N-tail lysines such as histone H3 lysines (H3K4, H3K9, H3K27 and H3K36) and a histone H4 lysine 20 (H4K20) is known to be crucially involved in transcription control. In histone H3, two residues (H3K64 and H3K79), located in the globular domains, and several lysine residues in H1, H2A and H2B, are also methylated, but the consequences of these modifications are poorly understood. H3K9, H3K27 and H4K20 methylation are inhibitory since they lead to transcriptional silence and heterochromatin formation and storage. By contrast, H3K4 and H3K36 methylation induce transcription (Berger 2007).
The relationship between histone posttranslational modification and DNA damage signaling and repair
Published in International Journal of Radiation Biology, 2019
Ajit K Sharma, Michael J. Hendzel
A chromatin environment that promotes transcription needs to be modified to reach a chromatin state that facilitates DNA repair in the presence of DNA damage. It has further been shown that H3K4me3, which is associated with transcriptional activation, is demethylated at DNA damage sites in human cells (Mosammaparast et al. 2013; Li X et al. 2014). KDM5B mediates demethylation of H3K4me2/me3 and also accumulates at I-Sce1-induced DSB sites in a PARP1 and macro-H2A1.1 dependent manner in human cells (Li X et al. 2014). Loss of KDM5B impairs the accumulation of the DSB repair factors Ku70 and BRCA1 at DSBs, which leads to defective NHEJ and HR repair. The functional role of mono- and di-methylation of H4K20 (H4K20me1/2) in DNA repair is well established. 53BP1 recognizes histone H4 lysine 20 methylation through its Tudor domain and is required for 53BP1 recruitment (Botuyan et al. 2006; Pei et al. 2011). In mammals, dimethylation of histone H4 lysine 20 (H4K20me2), is mediated by the histone methyltransferase MMSET (also known as NSD2 or WHSC1) (Pei et al. 2011). Interestingly, MMSET depletion significantly decreases H4K20 methylation at DSBs as well as 53BP1 accumulation at DSBs. Because histone H4K20 methylation is diluted by DNA replication, this hypomethylation of K20 may also serve to bias towards HR repair following DNA replication (Pellegrino et al. 2017). In addition, H4K20me2/3 is mediated by other KMTs (KMT5B/C or Suv4-20h1/2), which have also been shown to be involved in the DNA damage response (DDR). MEFs lacking these enzymes exhibit genome-wide transition to an H4K20me1 state, which results in increased sensitivity to DNA damaging agents and less efficient for DNA double-strand break (DSB) repair (Schotta et al. 2008).
Proteomic approaches for cancer epigenetics research
Published in Expert Review of Proteomics, 2019
Dylan M. Marchione, Benjamin A. Garcia, John Wojcik
Several subsequent MS-based studies also aimed to identify shared epigenetic changes across cancer cells. One study used stable isotope labeling and LC-MS/MS to comprehensively analyze the modifications on both histones H3 and H4 from a variety of breast cancer lines. Their results similarly demonstrated reduced levels of H4K16ac and H4K20me3 in the cancer cells relative to normal breast epithelium. They also revealed other consistent epigenetic changes, most notably an increase in H3K27me2/3 [39]. A subsequent analysis of 24 different cell lines likewise demonstrated a consistent elevation in H3K27me2/3 in cancer cells [40]. Interestingly, the latter study also included a microarray analysis of 224 histone-modifying genes, and found that the abundance of a given histone PTM did not always correlate with the abundance of the transcripts of the enzymes that regulate it, highlighting the importance of measuring the PTMs directly. The study also reported that two breast cancer lines displaying high levels of the EZH2 transcript and its catalytic byproducts H3K27me2/3 were particularly sensitive to EZH2 knockdown, demonstrating that profiling either the expression of histone modifiers, the abundance of specific histone PTMs, or both, might predict therapeutic vulnerabilities. While the underlying mechanism was not established, the authors noted that one way to do so would be to map where in the genome the PTM changes were localized via chromatin immunoprecipitation and high throughput sequencing (ChIP-seq), and then to cross-reference that data with a transcriptome analysis to identify affected genes [40]. Indeed, this has proven to be a powerful approach. An example of the suggested workflow is depicted in Figure 1.