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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
The first detection of transcription following fertilization occurs in the mouse zygote and is referred to as ZGA. This is unique among mammals as it occurs before the first cleavage division, with genome activation generally initiating in four- to eight-cell embryos and termed EGA (Figure 9.1b). Genome activation in the mouse is divided into the minor ZGA, occurring during the one-cell stage, and the major wave during the two-cell stage. The transcripts generated during the minor wave are rather promiscuous, low-level, and genome-wide, often resulting in transcripts that are inefficiently spliced and polyadenylated.62 Although the significance of the minor ZGA in the mouse remains unclear, and may reflect opportunistic transcription produced as the genomes are epigenetically reset, some significantly functional transcripts are produced. The D4Z4 repeats are located in the subtelomeric region of chr4q35 with each repeat unit containing the open reading frame for the DUX4 double-homeobox TF that acts as a transcriptional activator in both mice and humans.63 The D4Z4 repeats are normally highly methylated and enriched with H3K9me3, but during pre-implantation reprogramming, these marks are temporally depleted allowing for a burst of DUX4 expression.64,65 Chromatin immunoprecipitation experiments (ChIP-Seq) indicate that DUX preferentially binds to genes and endogenous retroviral elements (ERVs) that are specific for early stage embryos, with binding profiles overlapping intervals with chromatin accessibility.64 However, it is currently unknown if DUX acts as a pioneer factor, binding to heterochromatin and subsequently making it accessible, possibly through nucleosome remodeling and deposition of acetylation on histones.66 The DUX4 TF is not solely responsible for genome activation and other yet-to-be-identified pioneer factors/TFs must be involved. These may be maternally derived mRNAs that might be translationally upregulated, whereas others may be regulated at the level of transcription. In all cases, these early activators are not present at fertilization, suggesting their activity must be carefully controlled to prevent premature transcriptional activation.
Altitude, temperature, circadian rhythms and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Henning Wackerhage, Kenneth A. Dyar, Martin Schönfelder
In addition to a wide variety of metabolic genes and energy sensors, many muscle-specific genes cycle over 24 h, including Myod1, coding for the myogenic regulatory factor MyoD. During development, MyoD acts as a myocyte pioneer factor by opening closed chromatin at regulatory DNA sites in muscle-specific genes throughout the genome. After directing progenitor cells into a muscle cell-type lineage, MyoD maintains their differentiated state by keeping these sites open. Normally expressed at low levels in quiescent muscle stem cells (See Chapter 8 and 13), MyoD expression can become activated by exercise or damage, promoting muscle tissue remodelling and regeneration. Just like BMAL1, CLOCK and HIF-1α, MyoD is another basic helix-loop-helix transcription factor that can activate target genes after binding to similar “E-Box” DNA sequences in promoters and enhancers. Professor Karyn Esser’s group (Box 11.2) determined that Myod1 is also a direct CLOCK:BMAL1 target (94) and vice versa (83). This bidirectional regulation is thought to strengthen circadian alignment, and to amplify 24 h oscillation of other circadian clock-controlled muscle genes, including Telethonin (Tcap). This 24 h oscillating CLOCK:BMAL1 target gene is a Z-disc protein that regulates sarcomere assembly and T-tubule function. Intriguingly, muscles from ClockΔ19 mice (mutant mice have a point mutation that causes a deficiency in the 19th exon of the Clock gene) which are completely arrhythmic, show severely blunted 24 h Myod1 transcript and protein levels. This was associated with impaired muscle function, as specific force of extensor digitorum longus muscles was ~30% lower in ClockΔ19, Bmal1 knockout and Myod1 knockout mice compared to wildtype controls (94). However, 24 h Myod1 oscillation was reported to be increased in a muscle-specific Bmal1 knockout mouse model (77). These mice had normal 24 h activity and feeding patterns, yet also showed reduced force production in gastrocnemius muscles, and blunted oscillation of circadian genes, including Telethonin (95). These contrasting data suggest additional work is needed to clarify the roles of MyoD in driving circadian gene regulation in differentiated muscle tissue.
Gordon H. Dixon’s trace in my personal career and the quantic jump experienced in regulatory information
Published in Systems Biology in Reproductive Medicine, 2018
Competitive mechanisms are also involved in chromatin binding of ‘pioneer’ transcription factors, the first to bind enhancer elements during cell differentiation. Their binding is necessary to alter the epigenetic landscape, trigger transcriptional competency of enhancers, and implement cell type specific expression programs (Magnani et al. 2011). The prototypical pioneer factor fork-head box protein A1 (FOXA1, also known as HNF3α) contains a winged helix motif highly homologous to that of H1, and can efficiently displace H1 from chromatin (Cirillo et al. 1998, 2002). This displacement may constitute an obligatory first step of the transcriptional response to retinoic acid in ES cells (Taube et al. 2010). Finally, strong evidence exists for competition between human methyl CpG binding protein 2 (MeCP2) and H1 for common binding sites (Ghosh et al. 2010), which may be important for the combinatorial regulation of gene expression. Interestingly, the association of MeCP2 with oligonucleosomes appears to impact the zigzag architectural motif characteristic of H1 containing chromatin. Then, MeCP2 may interact with nucleosomes and be able to promote chromatin compaction (Ghosh et al. 2010).
PD-L1 and Notch as novel biomarkers in pancreatic sarcomatoid carcinoma: a pilot study
Published in Expert Opinion on Therapeutic Targets, 2021
Nicola Silvestris, Antonella Argentiero, Oronzo Brunetti, Margherita Sonnessa, Fulvia Colonna, Sabina Delcuratolo, Claudio Luchini, Aldo Scarpa, Sara Lonardi, Floriana Nappo, Matteo Fassan, Antonio Giovanni Solimando, Livia Fucci, Concetta Saponaro
PD-L1 over-expression represents a pioneer factor among predictive biomarkers of response to immune checkpoints inhibition in several tumors [31,32]. Furthermore, the Notch signaling pathway appears to play an emerging role in the regulation of PD-L1 expression in solid tumors [33–36]. In this scenario, the role of TME as a potential therapeutic target remains an unmet need, especially in the rare biologically poorly characterized malignancies.