Embryonic genome activation (EGA) in mammals begins with transient expression of a large group of genes (EGA1). Importantly, entry into and exit from the 2C/EGA state is essential for viability. Dux family member genes play an integral role in EGA1 by activating other EGA marker genes such as Zscan4 family members. We previously reported that structural maintenance of chromosomes flexible hinge domain-containing protein 1 ( Smchd1) is expressed at the mRNA and protein levels in mouse oocytes and early embryos and that elimination of Smchd1 expression inhibits inner cell mass formation, blastocyst formation and hatching, and term development. We extend these observations here by showing that siRNA knockdown of Smchd1 in zygotes results in overexpression of Dux and Zscan4 in two-cell embryos, with continued overexpression of Dux at least through the eight-cell stage as well as prolonged expression of Zscan4. These results are consistent with a role for SMCHD1 in promoting exit from the EGA1 state and establishing SMCHD1 as a maternal effect gene and the first chromatin regulatory factor identified with this role. Additionally, bioinformatics analysis reveals that SMCHD1 also contributes to the creation of a transcriptionally repressive state to allow correct gene regulation.
Structural maintenance of chromosome flexible domain containing 1 (Smchd1) is a chromatin regulatory gene for which mutations are associated with facioscapulohumeral muscular dystrophy and arhinia. The contribution of oocyte- and zygote-expressed SMCHD1 to early development was examined in mice ( Mus musculus) using a small interfering RNA knockdown approach. Smchd1 knockdown compromised long-term embryo viability, with reduced embryo nuclear volumes at the morula stage, reduced blastocyst cell number, formation and hatching, and reduced viability to term. RNA sequencing analysis of Smchd1 knockdown morulae revealed aberrant increases in expression of a small number of trophectoderm (TE)-related genes and reduced expression of cell proliferation genes, including S-phase kinase-associated protein 2 ( Skp2). Smchd1 expression was elevated in embryos deficient for Caudal-type homeobox transcription factor 2 ( Cdx2, a key regulator of TE specification), indicating that Smchd1 is normally repressed by CDX2. These results indicate that Smchd1 plays an important role in the preimplantation embryo, regulating early gene expression and contributing to long-term embryo viability. These results extend the known functions of SMCHD1 to the preimplantation period and highlight important function for maternally expressed Smchd1 messenger RNA and protein.
This work was supported by grants from the National Institutes of Health Office of Research Infrastructure Programs Division of Comparative Medicine Grants R24 [OD012221 to K.E.L., OD011107/RR00169 (California National Primate Research Center), and OD010967/RR025880 to C.A.V.]; the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under the award number T32HD087166; MSU AgBioResearch, Michigan State University. Authors have nothing to disclose.
The oocyte is a complex cell that executes many crucial and unique functions at the start of each life. These functions are fulfilled by a unique collection of macromolecules and other factors, all of which collectively support meiosis, oocyte activation, and embryo development. This review focuses on the effects of oocyte components on developmental processes that occur after the initial stages of embryogenesis. These include long-term effects on genome function, metabolism, lineage allocation, postnatal progeny health, and even subsequent generations.Factors that regulate chromatin structure, genome programming, and mitochondrial function are elements that contribute to these oocyte functions. K E Y W O R D S chromatin, embryo gene regulation, maternal effect, oocyte 400 |
Oocytes uniquely accumulate cytoplasmic constituents to support early embryogenesis. This unique specialization is accompanied by acquisition of a large size and by execution of asymmetric meiotic divisions that preserve precious ooplasm through the expulsion of minimal size polar bodies. While often taken for granted, these basic features of oogenesis necessitate unique specializations of the meiotic apparatus.
Maternal nutritional status programs the development of several systems in female offspring, with effects that depend on the severity, duration, and window of development when the nutritional perturbation is imposed. On the basis of the developmental origins of health and disease concept, we hypothesize that gestational low caloric intake may induce maternal subclinical hyperandrogenism during early pregnancy and compromise cardiovascular health and fertility in the female offspring. To examine this possibility, a literature search for human and animal studies was conducted using two electronic databases, PubMed and Cochrane until April 2019 to address the following questions: (a) Do androgens have a developmental role in cardiovascular and ovarian development? (b) Is excess maternal testosterone linked to cardiovascular disease and infertility? and (c) Could early pregnancy undernutrition enhance maternal androgen production and compromise health and fertility in female offspring? The observations reviewed, establish a potential causative link between maternal undernutrition and subclinical hyperandrogenism with hypertension and reduced ovarian reserve in the progeny. Further studies in appropriate models are needed to better understand whether low energy intake and subclinical maternal hyperandrogenism during early pregnancy can negatively affect the health of the female offspring.
What causes hybrid vigor phenotypes in mammalian oocytes and preimplantation embryos? Answering this question should provide new insight into determinants of oocyte and embryo quality and infertility. Hybrid vigor could arise through a variety of mechanisms, many of which must operate through posttranscriptional mechanisms affecting oocyte mRNA accumulation, stability, translation, and degradation. The differential regulation of such mRNAs may impact essential pathways and functions within the oocyte. We conducted in-depth transcriptome comparisons of immature and mature oocytes of C57BL/6J and DBA/2J inbred strains and C57BL/6J × DBA/2J F1 (BDF1) hybrid oocytes with RNA sequencing, combined with novel computational methods of analysis. We observed extensive differences in mRNA expression and regulation between parental inbred strains and between inbred and hybrid genotypes, including mRNAs encoding proposed markers of oocyte quality. Unique BDF1 oocyte characteristics arise through a combination of additive dominance and incomplete dominance features in the transcriptome, with a lesser degree of transgressive mRNA expression. Special features of the BDF1 transcriptome most prominently relate to histone expression, mitochondrial function, and oxidative phosphorylation. The study reveals the major underlying mechanisms that contribute to superior properties of hybrid oocytes in a mouse model.
The preimplantation period of life in mammals encompasses a tremendous amount of restructuring and remodeling of the embryonic genome and reprogramming of gene expression. These vast changes support metabolic activation and cellular processes that drive early cleavage divisions and enable the creation of the earliest primitive cell lineages. A major question in mammalian embryology is how such vast, sweeping changes in gene expression are orchestrated, so that changes in gene expression are exactly appropriate to meet the developmental needs of the embryo over time. Using the rhesus macaque as an experimentally tractable model species closely related to the human, we combined high quality RNA-seq libraries, in-depth sequencing and advanced systems analysis to discover the underlying mechanisms that drive major changes in gene regulation during preimplantation development. We identified the major changes in mRNA population and the biological pathways and processes impacted by those changes. Most importantly, we identified 24 key upstream regulators that are themselves modulated during development and that are associated with the regulation of over 1000 downstream genes. Through their roles in extensive gene networks, these 24 upstream regulators are situated to either drive major changes in target gene expression or modify the cellular environment in which other genes function, thereby directing major developmental transitions in the preimplantation embryo. The data presented here highlight some of the specific molecular features that likely drive preimplantation development in a nonhuman primate species and provides an extensive database for novel hypothesis-driven studies.
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