Science with Angela

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Week 3 in the books!

Hello my fellow Abstract Watchers! It was a beautiful, sunny week here in Park City, but I am in a definite rut, already just in week 3 of Abstract Watch. I am wondering if starting with one a day was too ambitious a goal out of the gate, even though it doesn't seem like much at all in theory (especially considering that I work on science writing every day..... or, perhaps it is because of that?). So, I set aside today to plow through 7 abstracts, which is a shame because it means I have to go through them kind of quickly and superficially. In part this is the skill I'm trying to build, but I do prefer a deep dive. Anyway - here we go!


Happy Reading!



AbstractWatch #14 Mouse embryo model derived exclusively from embryonic stem cells undergoes neurulation and heart development (preprint on biorxiv about 1 month earlier), from Dr. Magdalena Zernicka-Goetz's lab (full disclosure that I work quite a bit with Magda, and she is on the Board of the charity I co-founded, Life Science Editors Foundation). Magda's lab originally established conditions to grow 'complete' embryo models in vitro from three different stem cells: embryonic stem cells (ESC), trophoblast stem cells (TSC) and extraembryonic endoderm stem cells (XEN). These models capture the interactions between the epiblast (which will become the organism) and the two extraembryonic tissues (trophectoderm, which becomes the placenta, and extraembryonic endoderm, which becomes the yolk sac). In this paper they create an in vitro model completely from mouse ESCs that reconstitutes the pluripotent epiblast lineage and the two extraembryonic lineages of the post-implantation embryo. They combine unmodified ESCs with ESCs that are induced to express specific transcription factors (Cdx2 for the TSC-derived lineage, Gata4 for the XEN-derived lineage). Using conditions that were recently published from her group and others, this unified model could recapitulate developmental events from embryonic day 5.5 to 8.5, including gastrulation; formation of the anterior-posterior axis, brain, and a beating heart structure; and the development of extraembryonic tissues, including yolk sac and chorion. This breakthrough will help many labs take advantage of the full in vitro embryo model, given that ESCs are much more readily available than TSCs and XEN stem cells, and it will facilitate genetic and pharmacological manipulation of different lineages to tease apart their specific roles in early embryo development.


AbstractWatch #15 The conserved helicase ZNFX-1 memorializes silenced RNAs in perinuclear condensates (open access, no preprint) from Dr. Geraldine Seydoux's lab. RNA-mediated interference (RNAi) is a conserved mechanism that uses small RNAs (sRNAs) to silence gene expression. In the Caenorhabditis elegans germline, transcripts targeted by sRNAs are used as templates for sRNA amplification to propagate silencing into the next generation. Here we show that RNAi leads to heritable changes in the distribution of nascent and mature transcripts that correlate with two parallel sRNA amplification loops. The first loop, dependent on the nuclear Argonaute HRDE-1, targets nascent transcripts and reduces but does not eliminate productive transcription at the locus. The second loop, dependent on the conserved helicase ZNFX-1, targets mature transcripts and concentrates them in perinuclear condensates. ZNFX-1 interacts with sRNA-targeted transcripts that have acquired poly(UG) tails and is required to sustain pUGylation and robust sRNA amplification in the inheriting generation. This ZNFX-1 dependent second loop maintains a pool of transcripts for amplification, prevents premature extinction of the RNAi response and extends silencing into the next generation.


AbstractWatch #16 Escape from breast tumor dormancy: The convergence of obesity and menopause (no preprint, not open access) from Dr. Marsha Moses' lab. Postmenopausal obesity is associated with an increased risk of, and a poor prognosis for, breast cancer. Here, the authors wanted to determine the mechanism underlying this increased risk. The found that diet-induced obesity promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth. Using mouse models, they found that diet-induced obesity results in an earlier acquisition of the switch to the vascular phenotype (this is also called vascular mimicry: tumor cells form de novo perfusable vascular-like networks) and initiates aggressive tumor growth via increased neovascularization. Diet-induced obsesity establishes a local and systemic proangiogenic and inflammatory environment that may promote the escape from tumor dormancy and tumor progression.They show that targeting neovascularization via a multikinase angiogenesis inhibitor (sunitinib) delayed the switch to this phenotype, prolonged tumor latency, reduced tumor frequency, and increased tumor-free survival in obese postmenopausal mice. This study establishes the link between obesity and postmenopausal breast cancer and bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.


AbstractWatch #17 ER-Golgi-localized proteins TMED2 and TMED10 control the formation of plasma membrane lipid nanodomains (open access, no preprint) from Dr. F. Gisou van der Goot's lab.  Bacillus anthracis secrete anthrax toxin, which is composed of a cell-binding protein and two enzyme components. The cell-binding protein of anthrax toxin binds to a cellular receptor in cholesterol-rich lipid nanodomains, is cleaved, and oligomerizes. Oligomerization is required to translocate the enzyme components from endosomes to the cytosol. To identify genes involved in the toxin entry process, the authors used the anthrax toxin to screen a library of 1,500 regulatory, cell-surface, and membrane trafficking genes. They found that the endoplasmic reticulum (ER)-Golgi-localized proteins TMED2 and TMED10 are required for toxin oligomerization at the plasma membrane of human cells.They show that TMED2 and TMED10 are essential components of a supercomplex that operates lipid exchange at ER-Golgi membrane contact sites. Overall, they discovered TMED2 and TMED10 as key components of the molecular machinery necessary for the formation of functional plasma membrane lipid domains that are relevant for pathogen infection and fundamental physiological processes.


AbstractWatch #18 linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells (preprint, not yet published) from Dr. Antonio Giraldez's lab. Thousands of long intergenic non-coding RNAs (lincRNAs) are transcribed throughout the vertebrate genome. A subset of lincRNAs enriched in developing brains has recently been found to contain cryptic open reading frames and are speculated to encode micropeptides. However, systematic identification and functional assessment of these transcripts have been hindered by technical challenges caused by their small size. Here the authors show that two putative lincRNAs (linc-mipep and linc-wrb) encode micropeptides with homology to the vertebrate-specific chromatin architectural protein, Hmgn1, and demonstrate that they are required for development of vertebrate-specific brain cell types. They show that NMDA receptor-mediated pathways are dysregulated in zebrafish lacking these micropeptides and that their loss preferentially alters the gene regulatory networks that establish cerebellar cells and oligodendrocytes – evolutionarily newer cell types that develop postnatally in humans. These findings highlight that unexplored micropeptides might play an underappreciated role in the evolution of specific vertebrate brain cells.


AbstractWatch #19 CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1 (open access, not on biorxiv) from Dr. Dalibor Blazek's lab. RNA splicing is controlled by the spliceosome. Spliceosome activation is a major control step. Splicing factor 3B subunit 1 (SF3B1) is phosphorylated during spliceosome activation, but its kinase is unknown. Here the authors show that cyclin-dependent kinase 11 (CDK11) associates with SF3B1 and phosphorylates threonine residues at its N terminus during spliceosome activation. The phosphorylation is important for the association between SF3B1 and U5 and U6 snRNAs in the activated spliceosome, and the phosphorylation can be blocked by OTS964, a potent and selective inhibitor of CDK11. Inhibition of CDK11 prevents spliceosome activation and leads to widespread intron retention and accumulation of non-functional spliceosomes on pre-mRNAs and chromatin. Therefore CDK11 is required for spliceosome assembly, regulates splicing and OTS964 is a highly selective CDK11 inhibitor that suppresses spliceosome activation and splicing.


AbstractWatch #20 Endosome maturation links PI3Kα signaling to lysosome repopulation during basal autophagy (not on biorxiv, open access) from Dr. Christina Mitchell's lab. Autophagy depends on the repopulation of lysosomes to degrade intracellular components and recycle nutrients. How cells co-ordinate lysosome repopulation during basal autophagy, which occurs constitutively under nutrient-rich conditions, is unknown. Here, we identify an endosome-dependent phosphoinositide pathway that links PI3Kα signaling to lysosome repopulation during basal autophagy. We show that PI3Kα-derived PI(3)P generated by INPP4B on late endosomes was required for basal but not starvation-induced autophagic degradation. PI(3)P signals were maintained as late endosomes matured into endolysosomes, and served as the substrate for the 5-kinase, PIKfyve, to generate PI(3,5)P2. The SNX-BAR protein, SNX2, was recruited to endolysosomes by PI(3,5)P2 and promoted lysosome reformation. Inhibition of INPP4B/PIKfyve-dependent lysosome reformation reduced autophagic clearance of protein aggregates during proteotoxic stress leading to increased cytotoxicity. Therefore under nutrient-rich conditions, PI3Kα, INPP4B, and PIKfyve sequentially contribute to basal autophagic degradation and protection from proteotoxic stress via PI(3,5)P2-dependent lysosome reformation from endolysosomes. These findings reveal that endosome maturation couples PI3Kα signaling to lysosome reformation during basal autophagy.


"The woods are lovely, dark and deep"

Robert Frost