Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.

In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML

Compartmentalized PDE4A5 signaling impairs hippocampal synaptic plasticity and long-term memory

Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling

Transcriptomic Shock Generates Evolutionary Novelty in a Newly Formed, Natural Allopolyploid Plant

SummaryNew hybrid species might be expected to show patterns of gene expression intermediate to those shown by parental species [1, 2]. “Transcriptomic shock” may also occur, in which gene expression is disrupted; this may be further modified by whole genome duplication (causing allopolyploidy) [3–16]. “Shock” can include instantaneous partitioning of gene expression between parental copies of genes among tissues [16–19]. These effects have not previously been studied at a population level in a natural allopolyploid plant species. Here, we survey tissue-specific expression of 144 duplicated gene pairs derived from different parental species (homeologs) in two natural populations of 40-generation-old allotetraploid Tragopogon miscellus (Asteraceae) plants. We compare these results with patterns of allelic expression in both in vitro “hybrids” and hand-crossed F1 hybrids between the parental diploids T. dubius and T. pratensis, and with patterns of homeolog expression in synthetic (S1) allotetraploids. Partitioning of expression was frequent in natural allopolyploids, but F1 hybrids and S1 allopolyploids showed less partitioning of expression than the natural allopolyploids and the in vitro “hybrids” of diploid parents. Our results suggest that regulation of gene expression is relaxed in a concerted manner upon hybridization, and new patterns of partitioned expression subsequently emerge over the generations following allopolyploidization

Overview of the Kepler Science Processing Pipeline

The Kepler Mission Science Operations Center (SOC) performs several critical functions including managing the ~156,000 target stars, associated target tables, science data compression tables and parameters, as well as processing the raw photometric data downlinked from the spacecraft each month. The raw data are first calibrated at the pixel level to correct for bias, smear induced by a shutterless readout, and other detector and electronic effects. A background sky flux is estimated from ~4500 pixels on each of the 84 CCD readout channels, and simple aperture photometry is performed on an optimal aperture for each star. Ancillary engineering data and diagnostic information extracted from the science data are used to remove systematic errors in the flux time series that are correlated with these data prior to searching for signatures of transiting planets with a wavelet-based, adaptive matched filter. Stars with signatures exceeding 7.1 sigma are subjected to a suite of statistical tests including an examination of each star's centroid motion to reject false positives caused by background eclipsing binaries. Physical parameters for each planetary candidate are fitted to the transit signature, and signatures of additional transiting planets are sought in the residual light curve. The pipeline is operational, finding planetary signatures and providing robust eliminations of false positives.Comment: 8 pages, 3 figure