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The Epithelial to Mesenchymal Transition (EMT) regulates cell plasticity during embryonic development and in disease. It is dynamically orchestrated by transcription factors (EMT-TFs), including Snail, Zeb, Twist and Prrx, all activated by TGF-β among other signals. Here we find that Snail1 and Prrx1, which respectively associate with gain or loss of stem-like properties and with bad or good prognosis in cancer patients, are expressed in complementary patterns during vertebrate development and in cancer. We show that this complementarity is established through a feedback loop in which Snail1 directly represses Prrx1 , and Prrx1, through direct activation of the miR-15 family, attenuates the expression of Snail1. We also describe how this gene regulatory network can establish a hierarchical temporal expression of Snail1 and Prrx1 during EMT and validate its existence in vitro and in vivo, providing a mechanism to switch and select different EMT programs with important implications in development and disease. EMT is a developmental process that is aberrantly activated in metastasizing cancer cells, but how multiple transcription factors regulate EMT is unclear. Here, the authors uncover a gene regulatory network between Prrx1 and Snail1 that selects EMT mode in developing vertebrates and cancer cells.

The adult mammalian brain retains some capacity to replenish neurons and glia, holding promise for brain regeneration. Thus, understanding the mechanisms controlling adult neural stem cell (NSC) differentiation is crucial. Paradoxically, adult NSCs in the subependymal zone transcribe genes associated with both multipotency maintenance and neural differentiation, but the mechanism that prevents conflicts in fate decisions due to these opposing transcriptional programmes is unknown. Here we describe intron detention as such control mechanism. In NSCs, while multiple mRNAs from stemness genes are spliced and exported to the cytoplasm, transcripts from differentiation genes remain unspliced and detained in the nucleus, and the opposite is true under neural differentiation conditions. We also show that m 6 A methylation is the mechanism that releases intron detention and triggers nuclear export, enabling rapid and synchronized responses. m 6 A RNA methylation operates as an on/off switch for transcripts with antagonistic functions, tightly controlling the timing of NSCs commitment to differentiation. mRNAs associated with differentiated cells are already detected in adult neural stem cells. Here the authors show how intron detention prevents their translation, solving conflicts in fate decisions while priming stem cells for timely differentiation.

Cells must coordinate the activation of thousands of replication origins dispersed throughout their genome. Active transcription is known to favor the formation of mammalian origins, although the role that RNA plays in this process remains unclear. We show that the ORC1 subunit of the human Origin Recognition Complex interacts with RNAs transcribed from genes with origins in their transcription start sites (TSSs), displaying a positive correlation between RNA binding and origin activity. RNA depletion, or the use of ORC1 RNA-binding mutant, result in inefficient activation of proximal origins, linked to impaired ORC1 chromatin release. ORC1 RNA binding activity resides in its intrinsically disordered region, involved in intra- and inter-molecular interactions, regulation by phosphorylation, and phase-separation. We show that RNA binding favors ORC1 chromatin release, by regulating its phosphorylation and subsequent degradation. Our results unveil a non-coding function of RNA as a dynamic component of the chromatin, orchestrating the activation of replication origins. Here the authors describe that the human origin recognition complex subunit 1 (ORC1) binds to RNAs transcribed from genes with origins of replication at their TSS impacting origin activation.

Background Extreme acidic environments are characterized by their high metal content and lack of nutrients (oligotrophy). Macroscopic biofilms and filaments usually grow on the water-air interface or under the stream attached to solid substrates (streamers). In the Río Tinto (Spain), brown filaments develop under the water stream where the Gram-negative iron-oxidizing bacteria Leptospirillum spp. ( L. ferrooxidans and L. ferriphilum ) and Acidithiobacillus ferrooxidans are abundant. These microorganisms play a critical role in bioleaching processes for industrial (biominery) and environmental applications (acid mine drainage, bioremediation). The aim of this study was to investigate the physiological differences between the free living (planktonic) and the sessile (biofilm associated) lifestyles of Leptospirillum spp. as part of its natural extremely acidophilic community. Results Total RNA extracted from environmental samples was used to determine the composition of the metabolically active members of the microbial community and then to compare the biofilm and planktonic environmental transcriptomes by hybridizing to a genomic microarray of L. ferrooxidans . Genes up-regulated in the filamentous biofilm are involved in cellular functions related to biofilm formation and maintenance, such as: motility and quorum sensing ( mqsR, cheAY, fliA, motAB ), synthesis of cell wall structures ( lnt, murA, murB ), specific proteases ( clpX/clpP ), stress response chaperons ( clpB, clpC, grpE-dnaKJ, groESL ), etc. Additionally, genes involved in mixed acid fermentation ( poxB , ackA ) were up-regulated in the biofilm. This result, together with the presence of small organic acids like acetate and formate (1.36 mM and 0.06 mM respectively) in the acidic (pH 1.8) water stream, suggests that either L. ferrooxidans or other member of the microbial community are producing acetate in the acidophilic biofilm under microaerophilic conditions. Conclusions Our results indicate that the acidophilic filaments are dynamic structures in which different mechanisms for biofilm formation/dispersion are operating. Specific transcriptomic fingerprints can be inferred for both planktonic and sessile cells, having the former a more active TCA cycle, while the mixed acid fermentation process dominate in the latter. The excretion of acetate may play a relevant ecological role as a source of electron donor for heterotrophic Fe 3+ reducers like some Alphaproteobacteria, Acidobacterium spp. and Sulfobacillus spp., also present in the biofilm. Additionally, acetate may have a negative effect on bioleaching by inhibiting the growth of chemolithotrophic bacteria.

Eph receptor (Eph) and ephrin signaling regulate fundamental developmental processes through both forward and reverse signaling triggered upon cell–cell contact. In vertebrates, they are both classified into classes A and B, and some representatives have been identified in many metazoan groups, where their expression and functions have been well studied. We have extended previous phylogenetic analyses and examined the presence of Eph and ephrins in the tree of life to determine their origin and evolution. We have found that 1) premetazoan choanoflagellates may already have rudimental Eph/ephrin signaling as they have an Eph-/ephrin-like pair and homologs of downstream-signaling genes; 2) both forward- and reverse-downstream signaling might already occur in Porifera since sponges have most genes involved in these types of signaling; 3) the nonvertebrate metazoan Eph is a type-B receptor that can bind ephrins regardless of their membrane-anchoring structure, glycosylphosphatidylinositol, or transmembrane; 4) Eph/ephrin cross-class binding is specific to Gnathostomata; and 5) kinase-dead Eph receptors can be traced back to Gnathostomata. We conclude that Eph/ephrin signaling is of older origin than previously believed. We also examined the presence of protein domains associated with functional characteristics and the appearance and conservation of downstream-signaling pathways to understand the original and derived functions of Ephs and ephrins. We find that the evolutionary history of these gene families points to an ancestral function in cell–cell interactions that could contribute to the emergence of multicellularity and, in particular, to the required segregation of cell populations.

Epithelial-to-mesenchymal transition (EMT) triggers cell plasticity in embryonic development, adult injured tissues and cancer. Combining the analysis of EMT in cell lines, embryonic neural crest and mouse models of renal fibrosis and breast cancer, we find that there is not a cancer-specific EMT program. Instead, cancer cells dedifferentiate and bifurcate into two distinct and segregated cellular trajectories after activating either embryonic-like or adult-like EMTs to drive dissemination or inflammation, respectively. We show that SNAIL1 acts as a pioneer factor in both EMT trajectories, and PRRX1 drives the progression of the embryonic-like invasive trajectory. We also find that the two trajectories are plastic and interdependent, as the abrogation of the EMT invasive trajectory by deleting Prrx1 not only prevents metastasis but also enhances inflammation, increasing the recruitment of antitumor macrophages. Our data unveil an additional role for EMT in orchestrating intratumor heterogeneity, driving the distribution of functions associated with either inflammation or metastatic dissemination. Youssef et al. study epithelial-to-mesenchymal transition (EMT) programs in breast cancer and identify two interdependent trajectories coexisting within tumors, with EMT transcription factors such as PRRX1 at their nexus.

The DNA damage response (DDR) is a crucial signaling network that preserves the integrity of the genome. This network is an ensemble of distinct but often overlapping subnetworks, where different components fulfill distinct functions in precise spatial and temporal scenarios. To understand how these elements have been assembled together in humans, we performed comparative genomic analyses in 47 selected species to trace back their emergence using systematic phylogenetic analyses and estimated gene ages. The emergence of the contribution of posttranslational modifications to the complex regulation of DDR was also investigated. This is the first time a systematic analysis has focused on the evolution of DDR subnetworks as a whole. Our results indicate that a DDR core, mostly constructed around metabolic activities, appeared soon after the emergence of eukaryotes, and that additional regulatory capacities appeared later through complex evolutionary process. Potential key posttranslational modifications were also in place then, with interacting pairs preferentially appearing at the same evolutionary time, although modifications often led to the subsequent acquisition of new targets afterwards. We also found extensive gene loss in essential modules of the regulatory network in fungi, plants, and arthropods, important for their validation as model organisms for DDR studies.

The regulation of signal transduction by phosphorylation and ubiquitination is essential to ensure the correct behavior of eukaryotic cells. We searched for protein families involved in such signaling in several eukaryotic species and in a limited set of prokaryotes, where two members of the Planctomycetes phylum were included as they exhibit eukaryote-like features ( Gemmata obscuriglobus and Pirellula staleyi ). We identified sequences homologous to eukaryotic serine/threonine kinases (STKs) and E2-ubiquitin conjugating enzymes in the two Planctomycetes species. To extend these analyses to the Planctomycetes/Verrucomicrobia/Chlamydia super-phylum, we performed comparative analyses using domains from kinases, phosphatases and GTPases that serve as signaling signatures, and we analyzed their distributions. We found substantial differences in kinome densities with regards to other prokaryote clades and among the groups in the Planctomycetes/Verrucomicrobia/Chlamydia super-phylum. In addition, we identified the presence of classic eukaryotic E2-conjugating ubiquitin proteins in prokaryotes, these having previously believed to exist only in eukaryotes. Our phylogenetic analyses of the STKs signature domains and E2-enzymes suggest the existence of horizontal gene transfer.