MicroRNAs are frequently deregulated in cancer. Here we show that miR-22 is upregulated in myelodysplastic syndrome (MDS) and leukemia and its aberrant expression correlates with poor survival. To ...explore its role in hematopoietic stem cell function and malignancy, we generated transgenic mice conditionally expressing miR-22 in the hematopoietic compartment. These mice displayed reduced levels of global 5-hydroxymethylcytosine (5-hmC) and increased hematopoietic stem cell self-renewal accompanied by defective differentiation. Conversely, miR-22 inhibition blocked proliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developed MDS and hematological malignancies. We also identify TET2 as a key target of miR-22 in this context. Ectopic expression of TET2 suppressed the miR-22-induced phenotypes. Downregulation of TET2 protein also correlated with poor clinical outcomes and miR-22 overexpression in MDS patients. Our results therefore identify miR-22 as a potent proto-oncogene and suggest that aberrations in the miR-22/TET2 regulatory network are common in hematopoietic malignancies.
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•miR-22-TET2 regulatory network controls hematopoietic stem cell biology•miR-22 triggers myelodysplastic syndrome and hematological malignancies•Levels of miR-22 and TET2 are reliable prognostic factors in MDS patients
The microRNA miR-22 participates in the initiation of leukemia by targeting TET2 and high expression correlates with poor clinical outcomes, making it an attractive therapeutic target.
In this study, a constitutive model based on microscopic physical mechanism of silicone rubber foams was established. A theoretical statistical model of rubber elasticity considering the effect of ...dangling chains was modified to build this model. When a strain amplification factor (
X
) was introduced, the theoretical model could fit the tensile stress-strain data of mono- and bi-modal foam matrix well (Adj. R-Square = 0.9989, 0.9983). Parameters related to the polymer network, namely, average molecular weight (
M
c
) and volume fraction (
ϕ
) of chain segments between adjacent cross-linking points (network strands), were calculated by probabilistic method from the number-average molecular weight (
M
n
), vinyl content (
w
Vi
) of the primary polysiloxanes and percent conversion (
q
) of vinyl groups. The primary and infinite strain amplification factors (
X
0
,
X
∞
) and decay exponent (
z
), introduced by
X
and related to the nanoparticles, were obtained by fitting. Inspired by the fact that the actual strain of matrix was lower than that of the foams’, we introduced another item, strain hysteresis item (
H
, related with the foam porosity and cell structure), into the statistical model as well. With the same above values of
M
c
,
ϕ
,
X
0
and
X
∞
, the model could also fit the compressive stress-strain data of mono- and bi-modal foams well (Adj. R-Square = 0.9948, 0.9985). Interestingly, the strain hysteresis items of the mono- and bi-modal foams almost completely coincided under all experimental strains, which may be attributed to the almost equal porosity and similar cell structure of the two foams. This constitutive model may connect the macroscopic stress-strain behaviour to the parameters of microscopic molecular structures, promisingly providing a basis for the performance improvement and optimization of silicone rubber foams.
An emerging therapeutic strategy for cancer is to induce selective lethality in a tumor by exploiting interactions between its driving mutations and specific drug targets. Here we use a multi-species ...approach to develop a resource of synthetic lethal interactions relevant to cancer therapy. First, we screen in yeast ∼169,000 potential interactions among orthologs of human tumor suppressor genes (TSG) and genes encoding drug targets across multiple genotoxic environments. Guided by the strongest signal, we evaluate thousands of TSG-drug combinations in HeLa cells, resulting in networks of conserved synthetic lethal interactions. Analysis of these networks reveals that interaction stability across environments and shared gene function increase the likelihood of observing an interaction in human cancer cells. Using these rules, we prioritize ∼105 human TSG-drug combinations for future follow-up. We validate interactions based on cell and/or patient survival, including topoisomerases with RAD17 and checkpoint kinases with BLM.
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•We find a resource of conserved and divergent interactions for the design of cancer therapy•A global yeast screen directs network assembly in human cancer cells•As a rule, co-functionality and context stability predict translation to humans•There are many interactions involving clinically relevant genes, including BLM and XRCC3
An emerging strategy for precision cancer therapy is to induce synthetic lethality in a tumor based on its pattern of genetic mutations. Here we map a large network of conserved synthetic lethal interactions between selective drugs and tumor suppressor genes somatically mutated in human cancer. All of these interactions are mirrored in budding yeast, an accessible model for researching drug mode of action.
Efficient repair of UV-induced DNA damage requires the precise coordination of nucleotide excision repair (NER) with numerous other biological processes. To map this crosstalk, we generated a ...differential genetic interaction map centered on quantitative growth measurements of >45,000 double mutants before and after different doses of UV radiation. Integration of genetic data with physical interaction networks identified a global map of 89 UV-induced functional interactions among 62 protein complexes, including a number of links between the RSC complex and several NER factors. We show that RSC is recruited to both silenced and transcribed loci following UV damage where it facilitates efficient repair by promoting nucleosome remodeling. Finally, a comparison of the response to high versus low levels of UV shows that the degree of genetic rewiring correlates with dose of UV and reveals a network of dose-specific interactions. This study makes available a large resource of UV-induced interactions, and it illustrates a methodology for identifying dose-dependent interactions based on quantitative shifts in genetic networks.
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•Differential genetic analysis of 45,938 mutants was carried out in response to UV•Genetic data link RSC to global genome and transcription-coupled repair•RSC facilitates repair via nucleosome remodeling at sites of UV-induced lesions•High- and low-dose UV induce a set of dose-specific genetic interactions
The repair of UV-induced DNA damage requires the coordination of numerous cellular processes. In this study, Van Attikum, Ideker, and colleagues utilize differential epistasis mapping to uncover how the crosstalk between these processes are rewired in response to UV. The data pinpoint a role for the RSC complex in remodeling chromatin at the sites of UV damage to promote efficient repair. This study provides a first draft of the genetic networks governing the response to UV damage.
Acute myeloid leukemia (AML) is a highly diverse disease characterized by various cytogenetic and molecular abnormalities. MicroRNAs are small noncoding RNAs that show variable expression during ...myeloid differentiation. MicroRNA expression in marrow blasts in 215 cases of newly diagnosed and (cyto)genetically defined AML was assessed using quantitative reverse-transcription–polymerase chain reaction (RT-PCR) for 260 human microRNAs. In the same series, mRNA gene expression profiles were established, allowing a direct comparison between microRNA and mRNA expression. We show that microRNA expression profiling following unsupervised analysis reveals distinctive microRNA signatures that correlate with cytogenetic and molecular subtypes of AML (ie, AMLs with t(8;21), t(15;17), inv(16), NPM1, and CEBPA mutations). Significantly differentially expressed microRNAs for genetic subtypes of AML were identified. Specific microRNAs with established oncogenic and tumor suppressor functions, such as microRNA-155, microRNA-21, and let-7, appear to be associated with particular subtypes. Combinations of selected sets of microRNAs could predict cytogenetically normal AML with mutations in the genes of NPM1 and CEBPA and FLT3-ITD with similar accuracy as mRNA probe set combinations defined by gene expression profiling. MicroRNA expression apparently bears specific relationships to the heterogeneous pathobiology of AML. Distinctive microRNA signatures appear of potential value in the clinical diagnosis of AML.
Abstract
The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene ...expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity.
Eukaryotic chromosomes are replicated in interphase and the two newly duplicated sister chromatids are held together by the cohesin complex and several cohesin auxiliary factors. Sister chromatid ...cohesion is essential for accurate chromosome segregation during mitosis, yet has also been implicated in other processes, including DNA damage repair, transcription and DNA replication. To assess how cohesin and associated factors functionally interconnect and coordinate with other cellular processes, we systematically mapped the genetic interactions of 17 cohesin genes centered on quantitative growth measurements of >52,000 gene pairs in the budding yeast
Integration of synthetic genetic interactions unveiled a cohesin functional map that constitutes 373 genetic interactions, revealing novel functional connections with post-replication repair, microtubule organization and protein folding. Accordingly, we show that the microtubule-associated protein Irc15 and the prefoldin complex members Gim3, Gim4 and Yke2 are new factors involved in sister chromatid cohesion. Our genetic interaction map thus provides a unique resource for further identification and functional interrogation of cohesin proteins. Since mutations in cohesin proteins have been associated with cohesinopathies and cancer, it may also help in identifying cohesin interactions relevant in disease etiology.
In
Saccharomyces cerevisiae the Rad4-Rad23 complex is involved in initial damage recognition and responsible for recruiting the other NER proteins to the site of the lesion. The Rad4-Rad23 complex is ...essential for both NER subpathways, Transcription Coupled Repair (TCR) and Global Genome Repair (GGR). Previously, we reported on the role of the Rad4 homologue YDR314C in NER. YDR314C is essential for preferential repair of the transcribed strand in RNA pol I transcribed rDNA. In large scale interaction studies it was shown that YDR314C physically interacts with a small protein encoded by the ORF
YML011C. In the present study we show that YML011C is involved in NER and we propose to designate the YML011C ORF
RAD33. Cells deleted for
RAD33 display intermediate UV sensitivity that is epistatic with NER. Strand specific repair analysis shows that GGR in RNA pol II transcribed regions is completely defective in
rad33 mutants whereas TCR is still active, albeit much less efficient. In RNA pol I transcribed rDNA both GGR and TCR are fully dependent on Rad33. We show that in both
rad23 and
rad33 cells Rad4 and YDR314C protein levels are significantly reduced. The homology of YDR314C to Rad4, together with the similar relation of both proteins to Rad33 prompted us to propose
RAD34 as name for the
YDR314C gene. Although the
rad23rad33 double mutant is considerably more UV sensitive than a
rad23 or
rad33 single mutant, deletion of
RAD33 in a
rad23 background does not lead to a further reduction of Rad4 or Rad34 protein levels. This suggests that the role of Rad33 is not solely the stabilization of Rad4 and Rad34 but that Rad33 has an additional role in NER.
Cathode materials are the most critical challenge for the large scale application of Li-ion batteries in electric vehicles and for the storages of electricity. The first principles calculations play ...an important role in development and optimization of novel cathode materials. In this paper, we overview the first principles calculations of energy, volume change, band-gap, phase diagram, and Li-ion transport mechanism of cathode materials with an emphasis on the design of such materials. We also overview the recent progress of data mining techniques and the high-throughput first principles calculations for the design and development of cathode materials. Finally, we preview the challenges and opportunities of this rapidly developing field.
Eukaryotic chromosomes are replicated in interphase and the two newly duplicated sister chromatids are held together by the cohesin complex and several cohesin auxiliary factors. Sister chromatid ...cohesion is essential for accurate chromosome segregation during mitosis, yet has also been implicated in other processes, including DNA damage repair, transcription and DNA replication. To assess how cohesin and associated factors functionally interconnect and coordinate with other cellular processes, we systematically mapped genetic interactions of 17 cohesin genes centered on quantitative growth measurements of >52,000 gene pairs in budding yeast. Integration of synthetic genetic interactions unveiled a cohesin functional map that constitutes 373 genetic interactions, revealing novel functional connections with post-replication repair, microtubule organization and protein folding. Accordingly, we show that the microtubule-associated protein Irc15 and the prefoldin complex members Gim3, Gim4 and Yke2 are new factors involved in sister chromatid cohesion. Our genetic interaction map thus provides a unique resource for further identification and functional interrogation of cohesin proteins. Since mutations in cohesin proteins have been associated with cohesinopathies and cancer, it may also identify cohesin interactions relevant in disease etiology.
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