Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. ...However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusion target genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes.
The CHIME Pulsar Project: System Overview Amiri, M.; Bandura, K. M.; Boyle, P. J. ...
The Astrophysical journal. Supplement series,
07/2021, Letnik:
255, Številka:
1
Journal Article
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Abstract
We present the design, implementation, and performance of the digital pulsar observing system constructed for the Canadian Hydrogen Intensity Mapping Experiment (CHIME). Using accelerated ...computing, this system processes independent, digitally steered beams formed by the CHIME correlator to simultaneously observe up to 10 radio pulsars and transient sources. Each of these independent streams is processed by the CHIME/Pulsar back-end system, which can coherently dedisperse, in real time, up to dispersion measure values of 2500 pc cm
−3
. The tracking beams and real-time analysis system are autonomously controlled by a priority-based algorithm that schedules both known sources and positions of interest for observation with observing cadences as rapid as 1 day. Given the distribution of known pulsars and radio-transient sources and the dynamic scheduling, the CHIME/Pulsar system can monitor 400–500 positions once per sidereal day and observe most sources with declinations greater than −20° once every ∼4 weeks. We also discuss the extensive science program enabled through the current modes of data acquisition for CHIME/Pulsar that centers on timing and searching experiments.
A 70‐day experiment was conducted to investigate the optimal dietary macroalgae and substitute proportion by corn starch in juvenile sea cucumber Apostichopus japonicus. Sea cucumbers were fed by ...eighteen different diets formulated with one of the three macroalgae including Sargassum muticum, Gracilaria lemaneiformis and Ulva lactuca and six graded levels (0, 50, 100, 200, 300 and 400 g/kg) of corn starch as the replacements for each seaweed. An isotope mixing model indicated that the relative contribution of corn starch to the growth of A. japonicus did not consistently increase, even slightly decreased with increasing dietary corn starch level. The contributions of corn starch to A. japonicus fed by diets containing S. muticum were higher than those fed by diets containing G. lemaneiformis with corresponding corn starch levels or containing U. lactuca at 200–400 g/kg replacement proportions. The growth of A. japonicus first significantly increased and then decreased with increasing corn starch level, regardless of macroalgal species. The corn starch could replace up to 200 g/kg of dietary G. lemaneiformis or U. lactuca, even up to 300 g/kg of S. muticum without affecting growth performance. Based on the polynomial regression model, the replacement of S. muticum with 114 g/kg corn starch was optimal for A. japonicus.
Abstract
We report the discovery of seven new Galactic pulsars with the Canadian Hydrogen Intensity Mapping Experiment’s Fast Radio Burst (CHIME/FRB) backend. These sources were first identified via ...single pulses in CHIME/FRB, then followed up with CHIME/Pulsar. Four sources appear to be rotating radio transients, pulsar-like sources with occasional single-pulse emission with an underlying periodicity. Of those four sources, three have detected periods ranging from 220 ms to 2.726 s. Three sources have more persistent but still intermittent emission and are likely intermittent or nulling pulsars. We have determined phase-coherent timing solutions for the latter two. These seven sources are the first discovery of previously unknown Galactic sources with CHIME/FRB and highlight the potential of fast radio burst detection instruments to search for intermittent Galactic radio sources.
Aberrant activation of the three-amino-acid-loop extension homeobox gene MEIS1 shortens the latency and accelerates the onset and progression of acute leukemia, yet the molecular mechanism underlying ...persistent activation of the MEIS1 gene in leukemia remains poorly understood. Here we used a combined comparative genomics analysis and an in vivo transgenic zebrafish assay to identify six regulatory DNA elements that are able to direct green fluorescent protein expression in a spatiotemporal manner during zebrafish embryonic hematopoiesis. Analysis of chromatin characteristics and regulatory signatures suggests that many of these predicted elements are potential enhancers in mammalian hematopoiesis. Strikingly, one of the enhancer elements (E9) is a frequent integration site in retroviral-induced mouse acute leukemia. The genomic region corresponding to enhancer E9 is differentially marked by H3K4 monomethylation and H3K27 acetylation, hallmarks of active enhancers, in multiple leukemia cell lines. Decreased enrichment of these histone marks is associated with downregulation of MEIS1 expression during hematopoietic differentiation. Further, MEIS1/HOXA9 transactivate this enhancer via a conserved binding motif in vitro, and participate in an autoregulatory loop that modulates MEIS1 expression in vivo. Our results suggest that an intronic enhancer regulates the expression of MEIS1 in hematopoiesis and contributes to its aberrant expression in acute leukemia.
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