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The existence of discrete phenotypic traits suggests that the complex regulatory processes which produce them are functionally modular. These processes are usually represented by networks. Only modular networks can be partitioned into intelligible subcircuits able to evolve relatively independently. Traditionally, functional modularity is approximated by detection of modularity in network structure. However, the correlation between structure and function is loose. Many regulatory networks exhibit modular behaviour without structural modularity. Here we partition an experimentally tractable regulatory network—the gap gene system of dipteran insects—using an alternative approach. We show that this system, although not structurally modular, is composed of dynamical modules driving different aspects of whole-network behaviour. All these subcircuits share the same regulatory structure, but differ in components and sensitivity to regulatory interactions. Some subcircuits are in a state of criticality, while others are not, which explains the observed differential evolvability of the various expression features in the system.

Key Points A large fraction of genes in worms, flies and vertebrates express multiple mRNAs by alternative splicing. This produces extensive mRNA structural diversity that ultimately affects protein coding potential as well as mRNA cis -acting elements that are determinative for translation, mRNA stability and mRNA intracellular localization. Global analyses of alternative splicing regulation during periods of biological transition, such as during development, have revealed coordinated and conserved networks of alternative splicing. Several splicing regulatory networks controlled by individual RNA-binding proteins have been identified by combining recent advances in genome-wide analyses of alternative splicing with the identification of RNA binding sites in vivo . A high proportion of RNA-binding proteins that regulate alternative splicing are themselves regulated by alternative splicing and are subject to auto- and crossregulatory feedback. This type of regulation includes alternative splicing linked with nonsense-mediated decay (AS–NMD), which results in mRNA downregulation. Diverse physiological processes are regulated in a determinative fashion by alternative splicing patterns, including meiosis in budding yeast, neuronal arborization in the Drosophila melanogaster brain, and stem cell determination in vertebrates. The regulation of gene expression by alternative splicing is intricately linked with transcription, the epigenetic state of chromatin, and subsequent RNA processing events, such as 3′ end formation, mRNA export and mRNA translation efficiency. Recent transcriptomics studies have revealed extensive mRNA diversity generated by alternative splicing. An emerging theme is the existence of regulatory networks through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, involving robust and coordinated alternative splicing transitions. Genome-wide analyses of metazoan transcriptomes have revealed an unexpected level of mRNA diversity that is generated by alternative splicing. Recently, regulatory networks have been identified through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, which involve robust and coordinated alternative splicing transitions. The regulation of splicing in yeast, worms, flies and vertebrates affects a variety of biological processes. The functional classes of genes that are regulated by alternative splicing include both those with widespread homeostatic activities and those with cell-type-specific functions. Alternative splicing can drive determinative physiological change or can have a permissive role by providing mRNA variability that is used by other regulatory mechanisms.

Embryos in a particular phylum of the animal kingdom tend to most resemble one another at a stage in the middle of embryogenesis known as the phylotypic period; a transcriptional analysis of embryogenesis from single embryos of ten different phyla reveals that the transcripts expressed at the phylotypic stage (or mid-developmental transition) differ greatly between phyla, and a ‘phylum’ may be defined as a set of species sharing the same signals and transcription factor networks during the mid-developmental transition. Stage set for defining a phylum Embryos in a particular phylum tend to resemble one another closely at some point in the middle of embryogeny. This is known as the phylotypic stage, and it has been established that embryos at this stage tend to express a conserved set of genes that are evolutionarily older than the genes expressed before and after. This, however, only applies within a phylum, as Yanai and colleagues demonstrate in an analysis of transcriptomes from individual embryos of ten disparate phyla. Considered across the whole animal kingdom, the transcripts expressed at the phylotypic stage differ greatly between phyla and could be said to define the characters of a particular phylum. This work also provides an operational definition for a phylum as a set of species — with a common ancestor — that share the same molecular mechanisms at the phylotypic stage. Animals are grouped into ~35 ‘phyla’ based upon the notion of distinct body plans 1 , 2 , 3 , 4 . Morphological and molecular analyses have revealed that a stage in the middle of development—known as the phylotypic period—is conserved among species within some phyla 5 , 6 , 7 , 8 , 9 . Although these analyses provide evidence for their existence, phyla have also been criticized as lacking an objective definition, and consequently based on arbitrary groupings of animals 10 . Here we compare the developmental transcriptomes of ten species, each annotated to a different phylum, with a wide range of life histories and embryonic forms. We find that in all ten species, development comprises the coupling of early and late phases of conserved gene expression. These phases are linked by a divergent ‘mid-developmental transition’ that uses species-specific suites of signalling pathways and transcription factors. This mid-developmental transition overlaps with the phylotypic period that has been defined previously for three of the ten phyla, suggesting that transcriptional circuits and signalling mechanisms active during this transition are crucial for defining the phyletic body plan and that the mid-developmental transition may be used to define phylotypic periods in other phyla. Placing these observations alongside the reported conservation of mid-development within phyla, we propose that a phylum may be defined as a collection of species whose gene expression at the mid-developmental transition is both highly conserved among them, yet divergent relative to other species.

In mice, transcription initiates at the mid-one-cell stage and transcriptional activity dramatically increases during the two-cell stage, a process called zygotic gene activation (ZGA). Associated with ZGA is a marked change in the pattern of gene expression that occurs after the second round of DNA replication. To distinguish ZGA before and after the second-round DNA replication, the former and latter are called minor and major ZGA, respectively. Although major ZGA are required for development beyond the two-cell stage, the function of minor ZGA is not well understood. Transiently inhibiting minor ZGA with 5, 6-dichloro-1-β-D-ribofuranosyl-benzimidazole (DRB) resulted in the majority of embryos arresting at the two-cell stage and retention of the H3K4me3 mark that normally decreases. After release from DRB, at which time major ZGA normally occurred, transcription initiated with characteristics of minor ZGA but not major ZGA, although degradation of maternal mRNA normally occurred. Thus, ZGA occurs sequentially starting with minor ZGA that is critical for the maternal-to-zygotic transition.

Soybean (Glycine max) seed is primarily composed of a mature embryo that provides a major source of protein and oil for humans and other animals. Early in development, the tiny embryos grow rapidly and acquire large quantities of sugars from the liquid endosperm of developing seeds. An insufficient supply of nutrients from the endosperm to the embryo results in severe seed abortion and yield reduction. Hence, an understanding of the molecular basis and regulation of assimilate partitioning involved in early embryo development is important for improving soybean seed yield and quality. Here, we used expression profiling analysis to show that two paralogous sugar transporter genes from the SWEET (Sugars Will Eventually be Exported Transporter) family, GmSWEET15a and GmSWEET15b, were highly expressed in developing soybean seeds. In situ hybridization and quantitative real-time PCR showed that both genes were mainly expressed in the endosperm at the cotyledon stage. GmSWEET15b showed both efflux and influx activities for sucrose in Xenopus oocytes. In Arabidopsis (Arabidopsis thaliana), knockout of three AtSWEET alleles is required to see a defective, but not lethal, embryo phenotype, whereas knockout of both GmSWEET15 genes in soybean caused retarded embryo development and endosperm persistence, resulting in severe seed abortion. In addition, the embryo sugar content of the soybean knockout mutants was greatly reduced. These results demonstrate that the plasma membrane sugar transporter, GmSWEET15, is essential for embryo development in soybean by mediating Suc export from the endosperm to the embryo early in seed development.

Comprehensive information on the timing and location of gene expression is fundamental to our understanding of embryonic development and tissue formation. While high-throughput in situ hybridization projects provide invaluable information about developmental gene expression patterns for model organisms like Drosophila, the output of these experiments is primarily qualitative, and a high proportion of protein coding genes and most non-coding genes lack any annotation. Accurate data-centric predictions of spatio-temporal gene expression will therefore complement current in situ hybridization efforts. Here, we applied a machine learning approach by training models on all public gene expression and chromatin data, even from whole-organism experiments, to provide genome-wide, quantitative spatio-temporal predictions for all genes. We developed structured in silico nano-dissection, a computational approach that predicts gene expression in >200 tissue-developmental stages. The algorithm integrates expression signals from a compendium of 6,378 genome-wide expression and chromatin profiling experiments in a cell lineage-aware fashion. We systematically evaluated our performance via cross-validation and experimentally confirmed 22 new predictions for four different embryonic tissues. The model also predicts complex, multi-tissue expression and developmental regulation with high accuracy. We further show the potential of applying these genome-wide predictions to extract tissue specificity signals from non-tissue-dissected experiments, and to prioritize tissues and stages for disease modeling. This resource, together with the exploratory tools are freely available at our webserver http://find.princeton.edu, which provides a valuable tool for a range of applications, from predicting spatio-temporal expression patterns to recognizing tissue signatures from differential gene expression profiles.

The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type. Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone resorption. In osteolytic diseases such as rheumatoid arthritis, periodontitis, and osteoporosis, the balance is lost and changes in favor of bone resorption. Therefore, it is vital to elucidate the mechanisms of osteoclast formation and bone resorption. It has been reported that osteocytes express Receptor activator of nuclear factor κΒ ligand (RANKL), an essential factor for osteoclast formation. RANKL secreted by osteocytes is the most important factor for physiologically supported osteoclast formation in the developing skeleton and in pathological bone resorption such as experimental periodontal bone loss. TNF-α directly enhances RANKL expression in osteocytes and promotes osteoclast formation. Moreover, TNF-α enhances sclerostin expression in osteocytes, which also increases osteoclast formation. These findings suggest that osteocyte-related cytokines act directly to enhance osteoclast formation and bone resorption. In this review, we outline the most recent knowledge concerning bone resorption-related cytokines and discuss the osteocyte as the master regulator of bone resorption and effector in osteoclast formation.

The EMX (Empty Spiracles Homeobox) genes EMX1 and EMX2 are two homeodomain gene members of the EMX family of transcription factors involved in the regulation of various biological processes, such as cell proliferation, migration, and differentiation, during brain development and neural crest migration. They play a role in the specification of positional identity, the proliferation of neural stem cells, and the differentiation of certain neuronal cell phenotypes. In general, they act as transcription factors in early embryogenesis and neuroembryogenesis from metazoans to higher vertebrates. The EMX1 and EMX2 ’s potential as tumor suppressor genes has been suggested in some cancers. Our work showed that EMX1 / EMX2 act as tumor suppressors in sarcomas by repressing the activity of stem cell regulatory genes ( OCT4 , SOX2 , KLF4 , MYC , NANOG , NES , and PROM1 ). EMX protein downregulation, therefore, induced the malignance and stemness of cells both in vitro and in vivo. In murine knockout (KO) models lacking Emx genes, 3MC-induced sarcomas were more aggressive and infiltrative, had a greater capacity for tumor self-renewal, and had higher stem cell gene expression and nestin expression than those in wild-type models. These results showing that EMX genes acted as stemness regulators were reproduced in different subtypes of sarcoma. Therefore, it is possible that the EMX genes could have a generalized behavior regulating proliferation of neural crest-derived progenitors. Together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-altering populations or cancer stem cells, acting as tumor suppressors in sarcoma.

The authors report that TACE, the tumor necrosis factor-α–converting enzyme, regulates PNS myelination by affecting neuregulin-1 type III activity. Mice lacking TACE in motor neurons show hypermyelination. Tumor necrosis factor-α–converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo . We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS.

David Page and colleagues examine genes with bivalent chromatin modifications in male germ cells from five mammalian species and chicken. They find that the set of bivalently marked genes shared by all species represent evolutionarily ancient morphogenesis regulators, whereas genes showing lineage-specific bivalent marks act downstream of these core regulators. Changes in gene regulation frequently underlie changes in morphology during evolution, and differences in chromatin state have been linked with changes in anatomical structure and gene expression across evolutionary time. Here we assess the relationship between evolution of chromatin state in germ cells and evolution of gene regulatory programs governing somatic development. We examined the poised (H3K4me3/H3K27me3 bivalent) epigenetic state in male germ cells from five mammalian and one avian species. We find that core genes poised in germ cells from multiple amniote species are ancient regulators of morphogenesis that sit at the top of transcriptional hierarchies controlling somatic tissue development, whereas genes that gain poising in germ cells from individual species act downstream of core poised genes during development in a species-specific fashion. We propose that critical regulators of animal development gained an epigenetically privileged state in germ cells, manifested in amniotes by H3K4me3/H3K27me3 poising, early in metazoan evolution.