China
Africa
Explore chapters and articles related to this topic
Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
The mitochondrial ROS-generating enzyme NADPH oxidase 4 (Nox4) is also implicated in cellular senescence. High expression and activity of Nox4 are observed in senescent lung fibroblasts (Sanders et al. 2015). Nox4 gene is associated with the euchromatin marker acetylated H4 lysine 16 (H4K16Ac) and inversely associated with the heterochromatin marker trimethylated histone 4 at lysine 20 (H4K20Me3) (Sanders et al. 2015). ROS generated from Nox4 is a mediator of OIS (Weyemi et al. 2012).
Epigenetic Modifications of Histones
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
George Rasti, Alejandro Vaquero
Oocytes remain arrested during prophase of the first meiotic division (prophase-I) for decades in humans. This prophase-I arrest is highly conserved in metazoans and is critical for oocyte differentiation because allows the oocyte to accumulate maternal components to ensure completion of oogenesis and activation of the embryonic genome upon fertilization. The oocyte contains histone-bound maternal DNA acquired during oogenesis comprising PTMs related to stalled metaphase-II. The most important difference between the chromatin of oocytes and of somatic nuclei is the absence of somatic linker histone H1 in oocytes, which is replaced with a specific histone H1 variant whose function remains elusive. Moreover, the histone H4 acetylation pattern changes during oogenesis, whereby the levels of H4K8ac and H4K12ac decrease as the oocytes mature, while that of H4K16ac increases (Figure 2.1). Interestingly, HDAC1 and 2 are important regulators of oogenesis through gene repression. While HDAC2 is essential in oocyte development, HDAC1 is more responsible for cell-cycle regulation and zygotic development (29,30). In contrast, SIRT1 deficiency does not seem to alter oocyte production in female mice (31).
The Genetic Program of Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Xiufang Wang, Huanling Zhang, Libo Su, Zhanjun Lv
Histone acetylation directly affects the physical association of histones and DNA. Evidence suggests that the pattern of histone acetylation changes during normal aging. The global levels of H3K56ac decrease during replicative aging in yeast, while those of H4K16ac increase, resulting in de-silencing of telomeric repeats (Dang et al., 2009). Global H4K16ac levels reduce during normal aging and in a mouse model of Hutchinson–Gilford progeria syndrome (HGPS) and may be linked, at least in the progeroid model, to a decreased association of histone acetyltransferases (HAT) with the nuclear periphery (Krishnan et al., 2011). Following contextual fear conditioning, older mice cannot upregulate H4K12ac, a mark that accelerates transcriptional elongation (Hargreaves et al., 2009), in their hippocampus, and this relates to changed gene expression and memory impairment (Peleg et al., 2010). Alterations in histone acetylation may be a result and a cause of the failure of older cells to transduce external stimuli to downstream transcriptional responses, a process that is detrimental for rapid cell-to-cell signaling in the brain. Both HAT and deacetylases (HDAC) regulate life span and metabolic health. For example, H4K16ac is deacetylated by the sirtuin SIR263, and reduced SIR2 dosage prolongs life span in S. cerevisiae (Kaeberlein et al., 1999) by limiting aberrant recombination at the ribosomal DNA locus. More generally, sirtuins may have a pro-longevity role by promoting enhanced genomic stability (Mostoslavsky et al., 2006; Toiber et al., 2013; Van Meter et al., 2014).
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
Acetylation of histone H4 at lysine 16 is mediated by hMOF (Taipale et al. 2005) and depletion of hMOF in HeLa and HepG2 cells causes dramatic reduction of H4K16Ac, which leads to accumulation of cells in the G(2) and M phase of the cell cycle (Taipale et al. 2005). Furthermore, hMOF-depleted cells show an augmented number of p-ATM and γH2AX foci and have an impaired repair response to ionizing irradiation. Reduced H4K16 acetylation is associated with a defective DDR and DSB repair following ionizing radiation (IR) (Sharma GG et al. 2010). Depletion of hMOF also influences ATM activation and thus results in delayed appearance of IR induced γH2Ax foci (Sharma GG et al. 2010). Collectively, H4K16Ac plays an important role in the maintenance of genomic stability and is implicated in tumor formation (Fraga et al. 2005).
Glioma-induced SIRT1-dependent activation of hMOF histone H4 lysine 16 acetyltransferase in microglia promotes a tumor supporting phenotype
Published in OncoImmunology, 2018
Dalel Saidi, Mathilde Cheray, Ahmed M. Osman, Vassilis Stratoulias, Olle R. Lindberg, Xianli Shen, Klas Blomgren, Bertrand Joseph
Our attention was drawn to the acetylation of histone 4 at lysine 16 (H4K16ac), since this particular histone post-translational modification has been demonstrated to play an important role in the regulation of transcription.10 The acetylation level of H4K16 is regulated by the opposing effects of the histone acetyltransferase hMOF and the histone deacetylase sirtuin1 (SIRT1).11,12 SIRT1 and hMOF share common substrates like H4K16ac and p53, suggesting their joint participation in different cellular processes. Further, hMOF and SIRT1 are highly evolutionarily conserved enzymes.13,14 Both enzymes are of particular interest as they display quite diverse roles in various cellular processes. hMOF enzymatic activity has an extraordinary specificity for H4K16,15 suggesting that any process mediated through H4K16ac can potentially be influenced by hMOF. Previous observations suggest that hMOF and H4K16ac may be involved in tumorigenesis.16 Notably, recent studies identified that hMOF autoacetylation changes the surface charge of the protein and alters its binding to the nucleosome.17,18 Thereby, SIRT1 deacetylates hMOF and promotes its recruitment on the chromatin which highlights the dynamic interplay between both enzymes in regulating H4K16 acetylation.18
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.