Michael T McManus

University of California, San Francisco, San Francisco, California, United States

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Publications (158)1338.83 Total impact

  • Michael Boettcher, Michael T McManus
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    ABSTRACT: The most widely used approach for defining gene function is to reduce or completely disrupt its normal expression. For over a decade, RNAi has ruled the lab, offering a magic bullet to disrupt gene expression in many organisms. However, new biotechnological tools-specifically CRISPR-based technologies-have become available and are squeezing out RNAi dominance in mammalian cell studies. These seemingly competing technologies leave research investigators with the question: "Which technology should I use in my experiment?" This review offers a practical resource to compare and contrast these technologies, guiding the investigator when and where to use this fantastic array of powerful tools. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 05/2015; 58(4):575-585. DOI:10.1016/j.molcel.2015.04.028 · 14.46 Impact Factor
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    ABSTRACT: We examined the effect of biochar on the water-soluble arsenic (As) concentration and the extent of organochlorine degradation in a co-contaminated historic sheep-dip soil during a 180-d glasshouse incubation experiment. Soil microbial activity, bacterial community and structure diversity were also investigated. Biochar made from willow feedstock (Salix sp) was pyrolysed at 350 or 550°C and added to soil at rates of 10 g kg-1 and 20 g kg-1 (representing 30 t ha-1 and 60 t ha-1). The isomers of hexachlorocyclohexane (HCH) alpha-HCH and gamma-HCH (lindane), underwent 10-fold and 4-fold reductions in concentration as a function of biochar treatment. Biochar also resulted in a significant reduction in soil DDT levels (P < 0.01), and increased the DDE:DDT ratio. Soil microbial activity was significantly increased (P < 0.01) under all biochar treatments after 60 days of treatment compared to the control. 16S amplicon sequencing revealed that biochar-amended soil contained more members of the Chryseobacterium, Flavobacterium, Dyadobacter and Pseudomonadaceae which are known bioremediators of hydrocarbons. We hypothesise that a recorded short-term reduction in the soluble As concentration due to biochar amendment allowed native soil microbial communities to overcome As-related stress. We propose that increased microbiological activity (dehydrogenase activity) due to biochar amendment was responsible for enhanced degradation of organochlorines in the soil. Biochar therefore partially overcame the co-contaminant effect of As, allowing for enhanced natural attenuation of organochlorines in soil.
    PLoS ONE 04/2015; 10(4):e0125393. DOI:10.1371/journal.pone.0125393 · 3.53 Impact Factor
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    ABSTRACT: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
    Nature 02/2015; 518(7539):317-30. DOI:10.1038/nature14248 · 42.35 Impact Factor
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    ABSTRACT: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understa
    Nature 02/2015; 518(7539):317-330. · 42.35 Impact Factor
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    ABSTRACT: While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells.
    Nature Communications 02/2015; 6:6351. DOI:10.1038/ncomms7351 · 10.74 Impact Factor
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    ABSTRACT: Identification of microRNAs (miRNAs) that regulate lipid metabolism is important to advance the understanding and treatment of some of the most common human diseases. In the liver, a few key miRNAs have been reported that regulate lipid metabolism, but since many genes contribute to hepatic lipid metabolism, we hypothesized that other such miRNAs exist. To identify genes repressed by miRNAs in mature hepatocytes in vivo, we injected adult mice carrying floxed Dicer1 alleles with an adenoassociated viral vector expressing Cre recombinase specifically in hepatocytes. By inactivating Dicer in adult quiescent hepatocytes we avoided the hepatocyte injury and regeneration observed in previous mouse models of global miRNA deficiency in hepatocytes. Next, we combined gene and miRNA expression profiling to identify candidate gene/miRNA interactions involved in hepatic lipid metabolism, and validated their function in vivo using antisense oligonucleotides. A candidate gene that emerged from our screen was lipoprotein lipase (Lpl), which encodes an enzyme that facilitates cellular uptake of lipids from the circulation. Unlike in energy-dependent cells like myocytes, Lpl is normally repressed in adult hepatocytes. We identified miR-29a as the miRNA responsible for repressing Lpl in hepatocytes, and found that decreasing hepatic miR-29a levels causes lipids to accumulate in mouse livers. Conclusion: Our screen suggests several new miRNAs are regulators of hepatic lipid metabolism. We show that one of these, miR-29a, contributes to physiological lipid distribution away from the liver and protects hepatocytes from steatosis. Our results, together with miR-29a's known anti-fibrotic effect, suggest miR-29a is a therapeutic target in fatty liver disease. (Hepatology 2014).
    Hepatology 01/2015; 61(1). DOI:10.1002/hep.27379 · 11.19 Impact Factor
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    ABSTRACT: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
    Nature 01/2015; 518(7539):317-330. · 42.35 Impact Factor
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    Nature 01/2015; 518(7539):317-330. · 42.35 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):LB-122-LB-122. DOI:10.1158/1538-7445.AM2014-LB-122 · 9.28 Impact Factor
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    ABSTRACT: Four breeding lines (BLs) of white clover, which range in terms of their disposition to increase biomass in response to low or high phosphate (P) levels in soil, were evaluated further when grown hydroponically. BL 45 increased both fresh and dry weight in response to P-deprivation, while BL 49 displayed the same significant stimulation in response to sufficient P. However, when compared these lines did not accumulate any significantly higher levels of P, and all four lines showed the same changes to root:shoot ratio in response to P-deprivation, as well as the induction of both soluble and cell-wall-associated acid phosphatase activity. These results confirm that there is no direct relationship between growth (as an increase in biomass) and acid phosphatase activity and further some responses to P-deprivation may be common to all genetic backgrounds suggesting that they are not part of the intricate mechanisms governing these responses.
    Journal of Plant Nutrition 07/2014; 37(9). DOI:10.1080/01904167.2014.881873 · 0.54 Impact Factor
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    ABSTRACT: Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) holds enormous promise for regenerative medicine. To elucidate endogenous barriers limiting this process, we systematically dissected human cellular reprogramming by combining a genome-wide RNAi screen, innovative computational methods, extensive single-hit validation, and mechanistic investigation of relevant pathways and networks. We identify reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion. Specific a disintegrin and metalloproteinase (ADAM) proteins inhibit reprogramming, and the disintegrin domain of ADAM29 is necessary and sufficient for this function. Clathrin-mediated endocytosis can be targeted with small molecules and opposes reprogramming by positively regulating TGF-β signaling. Genetic interaction studies of endocytosis or ubiquitination reveal that barrier pathways can act in linear, parallel, or feedforward loop architectures to antagonize reprogramming. These results provide a global view of barriers to human cellular reprogramming.
    Cell 07/2014; 158(2):449-61. DOI:10.1016/j.cell.2014.05.040 · 33.12 Impact Factor
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    ABSTRACT: The historical treatment of livestock with arsenical-based pesticides has resulted in large areas of pastoral land being highly contaminated with arsenic. This study investigated the effect of biochar on soil microbial activity and arsenic phytoextraction in an arsenic-contaminated soil during a 180 d glasshouse experiment. Biochar made from willow feedstock (Salix sp) was pyrolysed at 350 and 550 °C (representing a low- and high-temperature biochar) and amended to soil at rates of 30 t ha−1 and 60 t ha−1 to 30 cm depth (10 and 20 g biochar kg−1 soil, respectively). Ryegrass (Lolium perenne L.) was seeded and plant growth was monitored. Soil microbial activity, quantified using the dehydrogenase activity (DHA) assay, was significantly increased (P < 0.01) under all biochar treatments. This increase was in excess of 100% after 30 d of treatment and was significantly higher (P < 0.05) than the control throughout the trial for 350 °C amended soils. The increase for the 550 °C amended soils relative to the control was greater than 70%. No negative effect of biochar amendments on ryegrass germination was observed. Biochar promoted a 2-fold increase in shoot dry weight (DW) and a 3-fold increase in root DW after 180 d under all biochar amendments and this was attributed, at least in part, to the fertility value of biochar. By increasing dose rates of biochar amendment from 30 t ha−1 to 60 t ha−1 shoot tissue of ryegrass extracted significantly higher (P < 0.05) concentrations of arsenic. Through extrapolation, 350 °C biochar-amended soils were estimated to have the potential to increase ryegrass sward DW growth by 0.68 t ha−1 compared to ryegrass grown on unamended soils. This would correspond to an increase in the extraction of total arsenic by 14,000 mg ha−1 compared to unamended soils and in doing so decreasing soil remediation times by over 50%. This investigation provides insight into the beneficial attributes of biochar in contaminated soil, and specifically that produced from willow wood, and its potential to reduce the time needed to remediate arsenic-contaminated soil. However, more studies are needed to understand the mechanisms through which these benefits are provided.
    Agriculture Ecosystems & Environment 06/2014; 191. DOI:10.1016/j.agee.2014.03.035 · 3.20 Impact Factor
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    ABSTRACT: Misfolded ER proteins are retrotranslocated into the cytosol for degradation via the ubiquitin-proteasome system. The human cytomegalovirus protein US11 exploits this ER-associated protein degradation (ERAD) pathway to downregulate HLA class I molecules in virus-infected cells, thereby evading elimination by cytotoxic T-lymphocytes. US11-mediated degradation of HLA class I has been instrumental in the identification of key components of mammalian ERAD, including Derlin-1, p97, VIMP and SEL1L. Despite this, the process governing retrotranslocation of the substrate is still poorly understood. Here using a high-coverage genome-wide shRNA library, we identify the uncharacterized protein TMEM129 and the ubiquitin-conjugating E2 enzyme UBE2J2 to be essential for US11-mediated HLA class I downregulation. TMEM129 is an unconventional C4C4-type RING finger E3 ubiquitin ligase that resides within a complex containing various other ERAD components, including Derlin-1, Derlin-2, VIMP and p97, indicating that TMEM129 is an integral part of the ER-resident dislocation complex mediating US11-induced HLA class I degradation.
    Nature Communications 05/2014; 5:3832. DOI:10.1038/ncomms4832 · 10.74 Impact Factor
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    ABSTRACT: miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation.
    PLoS ONE 05/2014; 9(5):e95486. DOI:10.1371/journal.pone.0095486 · 3.53 Impact Factor
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    ABSTRACT: This review examines two classes of organism that live in symbiosis; grasses and fungi. Specifically it deals with grasses of the tribe Hordeeae (formerly Triticeae) of the subfamily Poöideae and the Epichloë fungi of family Clavicipitaceae. Epichloë endophytes, particularly asexual forms, have important roles in pastoral agricultural systems in the Americas, Australia and New Zealand. Selected strains add value to some grass-based forage systems by providing both biotic and abiotic stress resistance. The importance of cereal grasses such as wheat, barley, rye and oats to human and animal nutrition and indeed to the foundation and maintenance of human civilisation is well documented. Both organism classes, Epichloë endophytes and cereal grasses, are of great importance in their own contexts. Here we seek to review these two classes of organism and examine the possibility of bringing them together in symbiosis with the ultimate goal of improving cereal production systems.
    Journal of Systematics and Evolution 05/2014; 52(6). DOI:10.1111/jse.12107 · 1.65 Impact Factor
  • Matthew J Hangauer, Susan Carpenter, Michael T McManus
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    ABSTRACT: Recent studies harnessing deep RNA sequencing coupled with other complementary data have revealed the complex nature of metazoan transcriptomes.
    Genome Biology 04/2014; 15(4):112. DOI:10.1186/gb4172 · 10.47 Impact Factor
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    ABSTRACT: Functional characterization of noncoding sequences is crucial for understanding the human genome and learning how genetic variation contributes to disease. 3' untranslated regions (UTRs) are an important class of noncoding sequences, but their functions remain largely uncharacterized. We developed a method for massively parallel functional annotation of sequences from 3' UTRs (fast-UTR) and used this approach to measure the effects of a total of >450 kilobases of 3' UTR sequences from >2,000 human genes on steady-state mRNA abundance, mRNA stability and protein production. We found widespread regulatory effects on mRNA that were coupled to effects on mRNA stability and protein production. Furthermore, we discovered 87 novel cis-regulatory elements and measured the effects of genetic variation within known and novel 3' UTR motifs. This work shows how massively parallel approaches can improve the functional annotation of noncoding sequences, advance our understanding of cis-regulatory mechanisms and quantify the effects of human genetic variation.
    Nature Biotechnology 03/2014; 32(4). DOI:10.1038/nbt.2851 · 39.08 Impact Factor
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    ABSTRACT: The microRNA miR-210 is a signature of hypoxia. We found robust increase in the abundance of miR-210 (>100-fold) in activated T cells, especially in the TH17 lineage of helper T cells. Hypoxia acted in synergy with stimulation via the T cell antigen receptor (TCR) and coreceptor CD28 to accelerate and increase Mir210 expression. Mir210 was directly regulated by HIF-1α, a key transcriptional regulator of TH17 polarization. Unexpectedly, we identified Hif1a as a target of miR-210, which suggested negative feedback by miR-210 in inhibiting HIF-1α expression. Deletion of Mir210 promoted TH17 differentiation under conditions of limited oxygen. In experimental colitis, miR-210 reduced the abundance of Hif1a transcripts and the proportion of cells that produced inflammatory cytokines and controlled disease severity. Our study identifies miR-210 as an important regulator of T cell differentiation in hypoxia, which can limit immunopathology.
    Nature Immunology 03/2014; 15(4). DOI:10.1038/ni.2846 · 24.97 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):B232-B232. DOI:10.1158/1535-7163.TARG-13-B232 · 6.11 Impact Factor
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    ABSTRACT: Phenotypic high-throughput chemical screens allow for discovery of small molecules that modulate complex phenotypes and provide lead compounds for novel therapies; however, identification of the mechanistically relevant targets remains a major experimental challenge. We report the application of sequential unbiased high-throughput chemical and ultracomplex small hairpin RNA (shRNA) screens to identify a distinctive class of inhibitors that target nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide, a crucial cofactor in many biochemical processes. The lead compound STF-118804 is a highly specific NAMPT inhibitor, improves survival in an orthotopic xenotransplant model of high-risk acute lymphoblastic leukemia, and targets leukemia stem cells. Tandem high-throughput screening using chemical and ultracomplex shRNA libraries, therefore, provides a rapid chemical genetics approach for seamless progression from small-molecule lead identification to target discovery and validation.
    Chemistry & biology 10/2013; DOI:10.1016/j.chembiol.2013.09.014 · 6.59 Impact Factor

Publication Stats

10k Citations
1,338.83 Total Impact Points

Institutions

  • 2005–2015
    • University of California, San Francisco
      • • Department of Microbiology and Immunology
      • • Diabetes Center
      • • Lung Biology Center
      • • Department of Medicine
      San Francisco, California, United States
  • 1996–2015
    • Massey University
      • • Institute of Fundamental Sciences
      • • Institute of Molecular BioSciences
      Palmerston North City, Manawatu-Wanganui, New Zealand
  • 2008–2013
    • CSU Mentor
      • Department of Medicine
      Long Beach, California, United States
  • 2002–2007
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 2005–2006
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 2004
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1998
    • The University of Western Ontario
      London, Ontario, Canada
  • 1995
    • Horticulture Institute of New Zealand
      Окленд, Auckland, New Zealand