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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Approaches to studying aging features of human oocytes that may predispose to aneuploidy have largely derived from transcriptional comparisons or immunocytological staining of factors identified in mouse oocytes or from human cell lines (57). The spindle assembly checkpoint (SAC) is essential in mouse oocytes to facilitate accurate chromosome segregation (107) and has been suggested to be affected by aging in human oocytes (108). Similarly, the removal of acetylation marks on histone H4K12 or H3K9 is important for chromosome compaction in human oocytes and is associated with aberrant meiosis (109,110). This higher level of histone H4 acetylation in oocytes from women of advanced maternal age (109) indicates a general decrease in the capacity of aged oocytes to remove histone acetylation marks. Collectively, several cellular and chromosomal factors conspire to cause the high levels of aneuploidy in human eggs. Understanding aneuploidy requires sophisticated approaches. A recent study of aneuploidy risk in human oocytes identified potential genetic variants in Aurora kinases that are important for correct chromosome attachment to the meiotic spindle (111). Although such mutations may be rare, precision medicine for women at risk of aneuploid conceptions may become a possibility (112).
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 current status of blood epigenetic biomarkers for dementia
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Peter D. Fransquet, Joanne Ryan
As there are several histone protein families, as well as variants within each family, histone nomenclature is an important consideration when reporting findings and importantly, to enable accurate comparisons across studies [167]. Due to the amount of variation, it is slightly more complex than naming miRNAs [172] or specific DNA methylation marks (user-defined [173], or specifically named probes [174]). For example, and to provide context for the studies below, H4K12 would refer to the H4 histone family, and K12 signifies that the 12th lysine residue is being measured for modification [175]. Further, H3K9me3 refers to the H3 histone family, where the 9th lysine residue has been trimethylated [176].
Epigenetic regulation in Alzheimer’s disease: is it a potential therapeutic target?
Published in Expert Opinion on Therapeutic Targets, 2021
Histone tail acetylation is so far the most investigated among histone PTMs in the postmortem AD brain regions [10]. The comparison of postmortem AD and control brain samples revealed a marked increase of HDAC6 protein levels in AD cortical and hippocampal regions [110]. A targeted proteomic approach revealed decreased levels of both H3K18 and H3K23 acetylation in the temporal lobe from AD patients compared to controls [111]. Increased HDAC2 levels were observed in hippocampal brain regions of AD patients and in two animal models of neurodegeneration, and linked to reduced histone acetylation and decreased expression of genes important for learning and memory [112]. Others observed increased levels of histone H3 and histone H4 protein levels, as well as increased H3 and H4 acetylation levels, in postmortem middle and inferior temporal gyri from AD samples [113]. A more recent histone acetylome-wide investigation of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from AD and matched control brains revealed 4,162 differential peaks between the two groups, and the differentially acetylated peaks included regions annotated to genes involved in the progression of Aβ and tau pathology (APP, PSEN1, PSEN2, and MAPT), and regions containing variants associated with sporadic late-onset AD [114]. A similar epigenome-wide association study investigating histone 3 lysine 9 acetylation (H3K9ac) levels in 669 aged human prefrontal cortices revealed that tau protein burden had a broad effect on the epigenome, affecting 5,990 H3K9ac sites, and similar findings were observed in two AD mouse models [115]. Indeed, a recent proteome analysis in postmortem AD and control temporal lobes revealed H3K27ac and H3K9ac as the main enrichments specific to AD, as well as up-regulation of chromatin-related genes in AD, including the HATs that mediate deposition of these marks [116]. Another recent study revealed decreased HATs and HDACs levels in the frontal cortex of postmortem end-stage AD brains compared to controls, whereas only HDAC1 was decreased in the hippocampus. Moreover, histone H3 acetylation levels were increased in cell nuclei mainly in the frontal cortex of AD patients [117]. Collectively, these studies point to impaired histone tail acetylation in postmortem AD brains, albeit with some differences likely resulting from the different brain regions and disease stages investigated [110–117]. In addition, increased acetylation of histone H4 at lysine 12 (H4K12) was observed in monocytes of transgenic AD mice as well as in monocytes of MCI individuals [118], and dysregulation of histone tail acetylation was detected in the brain regions of transgenic AD mice [119].