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In early mammalian embryos, it remains unclear how the first cell fate bias is initially triggered and amplified toward cell fate segregation. Here, we report that a long noncoding RNA, LincGET, is transiently and asymmetrically expressed in the nucleus of two- to four-cell mouse embryos. Overexpression of LincGET in one of the two-cell blastomeres biases its progeny predominantly toward the inner cell mass (ICM) fate. Mechanistically, LincGET physically binds to CARM1 and promotes the nuclear localization of CARM1, which can further increase the level of H3 methylation at Arginine 26 (H3R26me), activate ICM-specific gene expression, upregulate transposons, and increase global chromatin accessibility. Simultaneous overexpression of LincGET and depletion of Carm1 no longer biased embryonic fate, indicating that the effect of LincGET in directing ICM lineage depends on CARM1. Thus, our data identify LincGET as one of the earliest known lineage regulators to bias cell fate in mammalian 2-cell embryos.

Constructing accurate gene regulatory network s (GRNs), which reflect the dynamic governing process between genes, is critical to understanding the diverse cellular process and unveiling the complexities in biological systems. With the development of computer sciences, computational-based approaches have been applied to the GRNs inference task. However, current methodologies face challenges in effectively utilizing existing topological information and prior knowledge of gene regulatory relationships, hindering the comprehensive understanding and accurate reconstruction of GRNs. In response, we propose a novel graph neural network (GNN)-based Multi-Task Learning framework for GRN reconstruction, namely MTLGRN. Specifically, we first encode the gene promoter sequences and the gene biological features and concatenate the corresponding feature representations. Then, we construct a multi-task learning framework including GRN reconstruction , Gene knockout predict , and Gene expression matrix reconstruction. With joint training, MTLGRN can optimize the gene latent representations by integrating gene knockout information, promoter characteristics, and other biological attributes. Extensive experimental results demonstrate superior performance compared with state-of-the-art baselines on the GRN reconstruction task, efficiently leveraging biological knowledge and comprehensively understanding the gene regulatory relationships. MTLGRN also pioneered attempts to simulate gene knockouts on bulk data by incorporating gene knockout information. [ABSTRACT FROM AUTHOR]

This article discusses a study published in Cell Proliferation that investigates the changes in mRNA isoforms during zygotic genome activation (ZGA) in mice. ZGA is the first transcriptional event after fertilization and involves the degradation of maternal mRNA and the transcription of new mRNAs from the zygotic genome. The study compares the transcriptomes of embryos with different parental genomes and stages of development to identify differential alternative splicing and alternative promoter usage events. The findings suggest that there are specific patterns of mRNA isoforms generated from the paternal and maternal genomes during ZGA, providing insights into how sperm and oocyte genomes regulate mammalian development. The study also examines the differences in mRNA isoforms before and after ZGA in mice and humans, identifying changes that can have functional implications beyond differences in mRNA abundance. The study provides insights into the regulatory mechanisms involved in early embryonic development and suggests that isoform changes can serve as markers for ZGA events, although further validation is needed to understand the specific functions of each isoform. The study was supported by various funding sources and the authors declare no conflicts of interest. [Extracted from the article]

Graphical Abstract [ABSTRACT FROM AUTHOR]

SIRT6 acts as a longevity protein in rodents.sup.1,2. However, its biological function in primates remains largely unknown. Here we generate a SIRT6-null cynomolgus monkey (Macaca fascicularis) model using a CRISPR-Cas9-based approach. SIRT6-deficient monkeys die hours after birth and exhibit severe prenatal developmental retardation. SIRT6 loss delays neuronal differentiation by transcriptionally activating the long non-coding RNA H19 (a developmental repressor), and we were able to recapitulate this process in a human neural progenitor cell differentiation system. SIRT6 deficiency results in histone hyperacetylation at the imprinting control region of H19, CTCF recruitment and upregulation of H19. Our results suggest that SIRT6 is involved in regulating development in non-human primates, and may provide mechanistic insight into human perinatal lethality syndrome.A cynomolgus monkey model deficient in SIRT6 protein exhibits severe retardation in prenatal development, in which neuronal differentiation is delayed by activation of the H19 long non-coding RNA., Author(s): Weiqi Zhang [sup.1] [sup.2] [sup.3] [sup.4] , Haifeng Wan [sup.2] [sup.3] [sup.4] , Guihai Feng [sup.2] [sup.3] [sup.4] , Jing Qu [sup.2] [sup.3] [sup.4] , Jiaqiang Wang [sup.2] [sup.3] [...]

Metabolic programming is deeply intertwined with early embryonic development including zygotic genome activation (ZGA), the polarization of zygotic cells, and cell fate commitment. It is crucial to establish a noninvasive imaging technology that spatiotemporally illuminates the cellular metabolism pathways in embryos to track developmental metabolism in situ. In this study, we used two high‐quality genetically encoded fluorescent biosensors, SoNar for NADH/NAD+ and iNap1 for NADPH, to characterize the dynamic regulation of energy metabolism and redox homeostasis during early zygotic cleavage. Our imaging results showed that NADH/NAD+ levels decreased from the early to the late two‐cell stage, whereas the levels of the reducing equivalent NADPH increased. Mechanistically, transcriptome profiling suggested that during the two‐cell stage, zygotic cells downregulated the expression of genes involved in glucose uptake and glycolysis, and upregulated the expression of genes for pyruvate metabolism in mitochondria and oxidative phosphorylation, with a decline in the expression of two peroxiredoxin genes, Prdx1 and Prdx2. Collectively, with the establishment of in situ metabolic monitoring technology, our study revealed the programming of redox metabolism during ZGA. [ABSTRACT FROM AUTHOR]

The cover image is based on the Letter to the Editor mRNA isoform switches during mouse zygotic genome activation by Fan Li et al., https://doi.org/10.1111/cpr.13655. [ABSTRACT FROM AUTHOR]