Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the ␣2␤1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the ␣2␤1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the ␣2␤1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express ␣2␤1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.

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Condensins are broadly conserved chromosome organizers that function in chromatin compaction and transcriptional regulation, but to what extent these two functions are linked has remained unclear. Here, we analyzed the effect of condensin inactivation on genome compaction and global gene expression in the yeast by performing spike-in-controlled genome-wide chromosome conformation capture (3C-seq) and mRNA-sequencing analysis. 3C-seq analysis shows that acute condensin inactivation leads to a global decrease in close-range intrachromosomal interactions as well as more specific losses of interchromosomal tRNA gene clustering. In addition, a condensin-rich interaction domain between the ribosomal DNA and the centromere on chromosome XII is lost upon condensin inactivation. Unexpectedly, these large-scale changes in chromosome architecture are not associated with global changes in mRNA levels. Our data suggest that the global transcriptional program of proliferating is resistant to condensin inactivation and the associated profound changes in genome organization.

Condensin is a multi-subunit protein complex that belongs to the family of structural maintenance of chromosomes (SMC) complexes. Condensins regulate chromosome structure in a wide range of processes including chromosome segregation, gene regulation, DNA repair and recombination.Recent research defined the structural features and molecular activities of condensins, but it is unclear how these activities are connected to the multitude of phenotypes and functions attributed to condensins. In this review, we briefly discuss the different molecular mechanisms by which condensins may regulate global chromosome compaction, organization of topologically associated domains, clustering of specific loci such as tRNA genes, rDNA segregation, and gene regulation.

Acclimation to low O2 in many organisms involves changes at the level of the transcriptome. Here we used high-throughput RNA sequencing (RNA-Seq) to explore the global transcriptomic response and specific involvement of a suite of hemocyanin (Hc) subunits to low O2 alone and in combination with high CO2, which naturally co-occurs with low O2. Hepatopancreas mRNA of juvenile L. vannamei exposed to air-saturated water, low O2, or low O2/high CO2 for 4 or 24 h was pooled, sequenced (HiSeq 2500) and assembled (Trinity: 52,190 contigs) to create a deep strand-specific reference transcriptome. Annotation of the assembly revealed sequences encoding the previously described small Hc subunit (HcS), and three full-length isoforms of the large subunit (HcL1-3). In addition to this, a previously unidentified full-length Hc subunit was discovered. Phylogenetic analysis demonstrated the subunit to be a β-type Hc subunit (denoted HcB), making this the first report of a β-type hemocyanin subunit in the Penaeoidea. RNAs of individual shrimp were sequenced; regulated genes identified from pairwise comparisons demonstrated a distinct pattern of regulation between prolonged low O2 and low O2/high CO2 treatments by GO term enrichment analysis (Roff-Bentzen, P < 0.0001), showcasing the stabilization of energetically costly translational machinery, mobilization of energy stores, and downregulation of the ubiquitin/proteasomal degradation machinery. Exposure to hypoxia for 24 h resulted in an increase in all of the full-length hemocyanin subunits (HcS, HcL1, HcL2, HcL3, and HcB). The addition of CO2 to hypoxia muted the transcriptomic response of all the Hc subunits to low O2, except for the β-type subunit.

Tissue-specific somatic expansion of the mutant Huntingtin (mHTT) CAG tract and regional degeneration of the brain are key features of Huntington's disease (HD). However, the relationships between somatic CAG expansion, death of specific cell types, and molecular events associated with these processes have not been established. Here we employed fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. Expansion of the mHTT CAG tract occurs in striatal MSNs and cholinergic interneurons, in cerebellar Purkinje cells, and at the mutant ATXN3 locus in MSN nuclei from SCA3 donors. Somatic CAG tract instability in MSNs is associated with higher levels of MSH2 and MSH3. Our data indicate that somatic CAG tract expansion is not sufficient for cell death, and identify transcriptional changes associated with somatic CAG expansion and toxicity in the human striatum.

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The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular signals can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily postmitotic and aids regeneration in mammals. In the present study, we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of Yap target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.