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Epigenetics from Oocytes to Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Dagnė Daškevičiūtė, Marta Sanchez-Delgado, David Monk
Chromatin reorganization is critical for the reprogramming of the sperm- and oocyte-derived genomes into a pluripotent state. Open chromatin is tightly linked to transcriptional activation and is in part associated with repositioned or depleted nucleosomes and TF binding. Recently, studies using ATAC-seq (assay for transposase-accessible chromatin using sequencing) have revealed the landscape of chromatin accessibility during mouse development.56 In contrast to the asymmetries reported for 5mC and histone modifications, the two parental genomes seem to have a relatively synchronized chromatin profile, except at imprinted loci, with open chromatin located at CpG island promoters, which largely precedes EGA57 (Figure 9.1a, b).
Laboratory Molecular Methodologies to Analyze DNA Methylation
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Single-cell sequencing technologies have greatly helped dissect the heterogeneity of different cells present within a sample. In addition to scPBAT-seq and scRRBS, single-cell epigenome methods such as scHi-Seq, scChIP-seq, scDNAse1-seq, and scATAC-seq have revealed the wider epigenetic and chromatin heterogeneity in cell populations (41). All of these methods currently suffer from problems of spare coverage and poor signal-to-noise ratios. The simultaneous measurement of different layers of epigenetic information from the same cell remains challenging. One multi-omics protocol, Chromatin Overall Omics-scale Landscape sequencing (COOL-seq) allows for the assessment of chromatin accessibility, nucleosome positioning and DNA methylation (42). This method is essentially a scaled-down combination of Nucleosome Occupancy and Methylome sequencing (NOMe-seq), by which accessible chromatin is probes by sensitivity to methylation by the bacterial M.CviP1 methyltransferase, and scPBAT-seq, which has been shown to be sensitive and robust at the single-cell level.
Memory T cell, exhaustion, and tumor immunity
Published in Immunological Medicine, 2020
Makoto Ando, Minako Ito, Tanakorn Srirat, Taisuke Kondo, Akihiko Yoshimura
In a recent Nature paper, Chen et al. demonstrated that NR4a factors are deeply involved in T cell exhaustion (Figure 4). NR4a family factors are highly expressed in exhausted T cells in the tumor compared with the pre-exhausted stage in both humans and mice (Figure 2). NR4a up-regulates the inhibitory receptors PD-1 and TIM3, while it represses the IFNγ and TNFα expression. Overexpression of each NR4a factor exhibited gene expression profiles similar to those of exhausted T cells. T cells that are lacking all three NR4a transcription factors showed a reduced exhausted fraction, promoted tumor regression, and prolonged survival of tumor-bearing mice. ATAC-seq analysis defined that NR4a directly opens the chromatin of up-regulated genes by exhaustion, such as PD-1 and Tim3, while closes that of repressed genes that contain the binding motifs for NF-κB and AP-1 (Figure 4). Thus, NR4a transcription factors could be an important regulator of exhaustion and anergy, which are induced by chronic TCR signaling.
The role of proteomics in assessing beta-cell dysfunction and death in type 1 diabetes
Published in Expert Review of Proteomics, 2019
Ernesto S. Nakayasu, Wei-Jun Qian, Carmella Evans-Molina, Raghavendra G. Mirmira, Decio L. Eizirik, Thomas O. Metz
Proteomic analysis of a rat INS-1E cell line showed that IL-1β and IFN-γ regulate a large number of proteins related to insulin secretion, cytoskeleton organization, RNA metabolism, and ER and oxidative stress [47]. To better understand the mechanisms of cytokine-mediated regulation of β cells, Ramos-Rodriguez and colleagues performed a comprehensive multi-omics analysis of human islets and the human EndoC-βH1 cell line treated with the combination of IL-1β + IFN-γ and integrated the resulting data. The measurements included proteomics, chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq), DNA methylation analysis, assay for transposase-accessible chromatin sequencing (ATAC-seq), transcriptomics (RNA-seq), and genome-wise association study (GWAS). Such combination of techniques enabled the investigation of how cytokines promote chemical and physical changes in the structure of the chromatin, and whether these changes are associated with genomic loci with a higher risk of T1D and with consequent changes in mRNA and protein expression [48]. The study found two loci in genomic regions that are regulated by cytokines: rs78037977 in the region of the cytokine gene TNFSF18, and rs193778 in the region of the DEXI gene, which was shown to participate in β-cell death via cytokine signaling [49]. Importantly, the polymorphism in these loci was shown to have a strong effect on the expression of the respective genes [48].
Unveiling the Genomic Organization at GWAS Loci at Risk for Non-Syndromic Mitral Valve Prolapse
Published in Structural Heart, 2019
Sergiy Kyryachenko, Mengyao Yu, Adrien Georges, Russell Norris, Nabila Bouatia-Naji
Results: ATAC-seq data revealed profiles of chromatin accessibility that were consistent overall between dermal and cardiac fibroblasts. We then combined our data with publicly available ChIP-seq datasets for enhancer and promoter marks to define regulatory regions enriched at associated loci. We decided to explore the intronic SMG6 locus since it is known as a risk locus for several cardiovascular traits, including MVP, and our previous functional studies, including zebrafish knockdown of 2 candidates, SMG6 and SGSM2, failed to support their role in valve development. We found an abundance of potential regulatory regions at this locus. Using 3C experiments in cardiac fibroblasts, we demonstrate that the top associated variant physically interacts with unexplored proximal and distal genes with relevant candidate function.