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Dive into the research topics where Bryan D. Bryson is active.

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Featured researches published by Bryan D. Bryson.


Nature | 2013

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling

Scott R. Floyd; Michael E. Pacold; Qiuying Huang; Scott M. Clarke; Fred C. Lam; Ian G. Cannell; Bryan D. Bryson; Jonathan Rameseder; Michael J. Lee; Emily J. Blake; Anna Fydrych; Richard Ho; Benjamin Aaron Greenberger; Grace Chen; Amanda Maffa; Amanda M. Del Rosario; David E. Root; Anne E. Carpenter; William C. Hahn; David M. Sabatini; Clark C. Chen; Forest M. White; James E. Bradner; Michael B. Yaffe

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.


Molecular & Cellular Proteomics | 2012

Molecular Characterization of EGFR and EGFRvIII Signaling Networks in Human Glioblastoma Tumor Xenografts

Hannah Johnson; Amanda M. Del Rosario; Bryan D. Bryson; Mark A. Schroeder; Jann N. Sarkaria; Forest M. White

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with a mean survival of 15 months with the current standard of care. Genetic profiling efforts have identified the amplification, overexpression, and mutation of the wild-type (wt) epidermal growth factor receptor tyrosine kinase (EGFR) in ∼50% of GBM patients. The genetic aberration of wtEGFR is frequently accompanied by the overexpression of a mutant EGFR known as EGFR variant III (EGFRvIII, de2–7EGFR, ΔEGFR), which is expressed in 30% of GBM tumors. The molecular mechanisms of tumorigenesis driven by EGFRvIII overexpression in human tumors have not been fully elucidated. To identify specific therapeutic targets for EGFRvIII driven tumors, it is important to gather a broad understanding of EGFRvIII specific signaling. Here, we have characterized signaling through the quantitative analysis of protein expression and tyrosine phosphorylation across a panel of glioblastoma tumor xenografts established from patient surgical specimens expressing wtEGFR or overexpressing wtEGFR (wtEGFR+) or EGFRvIII (EGFRvIII+). S100A10 (p11), major vault protein, guanylate-binding protein 1(GBP1), and carbonic anhydrase III (CAIII) were identified to have significantly increased expression in EGFRvIII expressing xenograft tumors relative to wtEGFR xenograft tumors. Increased expression of these four individual proteins was found to be correlated with poor survival in patients with GBM; the combination of these four proteins represents a prognostic signature for poor survival in gliomas. Integration of protein expression and phosphorylation data has uncovered significant heterogeneity among the various tumors and has highlighted several novel pathways, related to EGFR trafficking, activated in glioblastoma. The pathways and proteins identified in these tumor xenografts represent potential therapeutic targets for this disease.


Methods | 2013

Computer aided manual validation of mass spectrometry-based proteomic data

Timothy G. Curran; Bryan D. Bryson; Michael Reigelhaupt; Hannah Johnson; Forest M. White

Advances in mass spectrometry-based proteomic technologies have increased the speed of analysis and the depth provided by a single analysis. Computational tools to evaluate the accuracy of peptide identifications from these high-throughput analyses have not kept pace with technological advances; currently the most common quality evaluation methods are based on statistical analysis of the likelihood of false positive identifications in large-scale data sets. While helpful, these calculations do not consider the accuracy of each identification, thus creating a precarious situation for biologists relying on the data to inform experimental design. Manual validation is the gold standard approach to confirm accuracy of database identifications, but is extremely time-intensive. To palliate the increasing time required to manually validate large proteomic datasets, we provide computer aided manual validation software (CAMV) to expedite the process. Relevant spectra are collected, catalogued, and pre-labeled, allowing users to efficiently judge the quality of each identification and summarize applicable quantitative information. CAMV significantly reduces the burden associated with manual validation and will hopefully encourage broader adoption of manual validation in mass spectrometry-based proteomics.


Development | 2014

SirT1 is required in the male germ cell for differentiation and fecundity in mice

Eric L. Bell; Ippei Nagamori; Eric O. Williams; Amanda M. Del Rosario; Bryan D. Bryson; Nicki Watson; Forest M. White; Paolo Sassone-Corsi; Leonard Guarente

Sirtuins are NAD+-dependent deacylases that regulate numerous biological processes in response to the environment. SirT1 is the mammalian ortholog of yeast Sir2, and is involved in many metabolic pathways in somatic tissues. Whole body deletion of SirT1 alters reproductive function in oocytes and the testes, in part caused by defects in central neuro-endocrine control. To study the function of SirT1 specifically in the male germ line, we deleted this sirtuin in male germ cells and found that mutant mice had smaller testes, a delay in differentiation of pre-meiotic germ cells, decreased spermatozoa number, an increased proportion of abnormal spermatozoa and reduced fertility. At the molecular level, mutants do not have the characteristic increase in acetylation of histone H4 at residues K5, K8 and K12 during spermiogenesis and demonstrate corresponding defects in the histone to protamine transition. Our findings thus reveal a germ cell-autonomous role of SirT1 in spermatogenesis.


Proteomics | 2015

Engineered bromodomains to explore the acetylproteome

Bryan D. Bryson; Amanda M. Del Rosario; Jonathan S. Gootenberg; Michael B. Yaffe; Forest M. White

MS‐based analysis of the acetylproteome has highlighted a role for acetylation in a wide array of biological processes including gene regulation, metabolism, and cellular signaling. To date, anti‐acetyllysine antibodies have been used as the predominant affinity reagent for enrichment of acetyllysine‐containing peptides and proteins; however, these reagents suffer from high nonspecific binding and lot‐to‐lot variability. Bromodomains represent potential affinity reagents for acetylated proteins and peptides, given their natural role in recognition of acetylated sequence motifs in vivo. To evaluate their efficacy, we generated recombinant proteins representing all known yeast bromodomains. Bromodomain specificity for acetylated peptides was determined using degenerate peptide arrays, leading to the observation that different bromodomains display a wide array of binding specificities. Despite their relatively weak affinity, we demonstrate the ability of selected bromodomains to enrich acetylated peptides from a complex biological mixture prior to mass spectrometric analysis. Finally, we demonstrate a method for improving the utility of bromodomain enrichment for MS through engineering novel affinity reagents using combinatorial tandem bromodomain pairs.


PLOS ONE | 2015

Quantitative Profiling of Lysine Acetylation Reveals Dynamic Crosstalk between Receptor Tyrosine Kinases and Lysine Acetylation.

Bryan D. Bryson; Forest M. White

Lysine acetylation has been primarily investigated in the context of transcriptional regulation, but a role for acetylation in mediating other cellular responses has emerged. Multiple studies have described global lysine acetylation profiles for particular biological states, but none to date have investigated the temporal dynamics regulating cellular response to perturbation. Reasoning that lysine acetylation may be altered in response to growth factors, we implemented quantitative mass spectrometry-based proteomics to investigate the temporal dynamics of lysine acetylation in response to growth factor stimulation in cultured carcinoma cell lines. We found that lysine acetylation changed rapidly in response to activation of several different receptor tyrosine kinases by their respective ligands. To uncover the effects of lysine acetylation dynamics on tyrosine phosphorylation signaling networks, cells were treated with an HDAC inhibitor. This short-term pharmacological inhibition of histone deacetylase activity modulated signaling networks involving phosphorylated tyrosine and thereby altered the response to receptor tyrosine kinase activation. This result highlights the interconnectivity of lysine acetylation and tyrosine phosphorylation signaling networks and suggests that HDAC inhibition may influence cellular responses by affecting both types of post-translational modifications.


Molecular Systems Biology | 2012

Signaling for death: tyrosine phosphorylation in the response to glucose deprivation.

Bryan D. Bryson; Forest M. White

The shift from oxidative phosphorylation to aerobic glycolysis in cancer has focused attention on the altered metabolism of cancer cells as a means of therapeutic intervention. Metabolic dysregulation in cancer was first proposed by Warburg in the 1930s, and this topic remains an active area of research. While previous studies have explored the connection between cellular signaling and metabolism, many have focused on a small subset of components within a complex network of proteins, enzymes, and biochemical signals. In a recent article published in Molecular Systems Biology, Graham et al (2012) endeavor to better understand the relationship between metabolism and signaling at the network level. Although the question of how cancer cells respond to glucose starvation posited by the authors is relatively simple, the answer ends up being unexpectedly complex. To answer this question, the authors use mass spectrometry and other biochemical profiling techniques to demonstrate a connection between glucose levels, reactive oxygen species (ROS), and alterations in phosphotyrosine-mediated signaling in glioblastoma cell lines. A number of previous studies have suggested a link between post-translational modifications and signaling in the cell metabolic network. For example, oncogenic tyrosine kinases can localize to the mitochondria providing an avenue whereby metabolic enzymes can be phosphorylated (Hitosugi et al, 2011), and phosphorylation of metabolic enzymes have been observed to regulate enzymatic activity (Christofk et al, 2008; Hitosugi et al, 2009; Fan et al, 2011). These findings help set the stage for the systems-level analysis performed by Graham et al (2012). Graham et al (2012) screened multiple cancer cell lines to determine their sensitivity to glucose starvation, and then assessed the cross-talk between metabolism and signaling. Using mass spectrometry, the authors found that cells sensitive to glucose withdrawal had increased tyrosine phosphorylation levels on many proteins following glucose starvation, suggesting a link between metabolism, signaling, and cellular response. Probing the signaling network further, the authors noted increased phosphorylation on a number of tyrosine kinases. To assess the mechanism driving this unexpected result, the authors quantified ROS, which had been previously implicated in mediating the cellular response to glucose withdrawal (Ahmad et al, 2005). As expected, they observed increased ROS levels following glucose deprivation, and inhibition of ROS activity ablated the dynamic phosphorylation response to glucose withdrawal. To explore the mechanism underlying this effect, the authors measured reduced levels of tyrosine phosphatase activity on glucose withdrawal; this reduction is presumably due to increased oxidation of the active site cysteine, known to decrease the activation state of these enzymes. Moreover, chemically inhibiting phosphatase activity in these cells was shown to increase ROS levels, which the authors propose creates a positive feedback loop amplifying this response. Taken in sum, the authors report a mechanism where glucose withdrawal induced increased levels of ROS that in turn inactivated tyrosine phosphatases and drove supraphysiological levels of tyrosine phosphorylation, which may amplify the feedback loop of further ROS production and tyrosine kinase signaling, finally ending with cell death (Figure 1). Figure 1 Glucose withdrawal initiates a complex molecular response resulting in decreased cell viability. Cells detect decreased glucose levels through an unknown sensor, which stimulates an increase in reactive oxygen species from the mitochondria. Increased ... The increased phosphorylation, after glucose withdrawal, of activating sites on receptor tyrosine kinases is a striking result given the typical correlation between increased tyrosine kinase signaling and cell growth. Some studies, however, have suggested a delicate balance within signaling networks, including at least two that have demonstrated that activation of Erk, a pro-growth MAPK kinase, can lead to cell death in certain contexts (Huang et al, 2010; Tentner et al, 2012). The mechanism by which increased tyrosine phosphorylation reduces cell viability in these glioblastoma cells remains to be determined, and could lead to insights into a potential avenue for cancer treatment, but there remains a significant amount of work to understand this behavior broadly. One question unaddressed by the authors is the mechanism by which the cells are receiving and transmitting the low-glucose signal. Some studies have implicated glucokinase and AMPK as critical mediators of glucose sensation (Matschinsky, 1990). Although no differences were observed in phosphorylation of acetyl-CoA carboxylase, a well-characterized substrate of AMPK, the activation state of AMPK was not directly tested, and therefore cannot be ruled out as a glucose-response trigger. It is likely that an alternate sensor may be responsible for transmitting the low-glucose signal to the enzymes involved in the generation of ROS, but at this point the identity of this sensor is still unknown. Activation of this sensor may be an interesting mechanism to transmit a low-glucose signal into cells as a potential therapeutic intervention. Other important questions remain, including whether a similar response can be observed in normal cells, and what molecular differences determine sensitivity and resistance to glucose withdrawal. The authors provide evidence that PTEN contributes to sensitivity in the LN229 cell line, but they do not fully address the molecular determinants of resistance. In addition, the mechanism underlying cell death in the sensitive cells will require more investigation, since the current experiments cannot distinguish between necrotic and apoptotic cells. While the glucose reduction experiment demonstrates the possibility of killing cancer cells through glucose deprivation in vitro, recapitulating this putative therapeutic response in vivo is quite difficult. To this end, it will be important to identify the signals responsible for reduction in cell viability. Future studies should consider the integration of the high-content phosphorylation data sets generated by techniques such as quantitative mass spectrometry with computational approaches to identify specific phosphorylation sites correlated with reduced viability. Recent studies have also implicated other post-translational modifications such as lysine acetylation as critical regulators of metabolic enzyme activity (Zhao et al, 2010). In the future, it will be important to incorporate additional PTMs into the signaling framework underlying glucose deprivation response. Once identified, perturbation of these signals may prove to be the more tenable means of biochemically mimicking the effects of glucose withdrawal. In summary, Graham et al (2012) demonstrate the novel and intriguing finding that perturbation of glucose levels leads to altered tyrosine phosphorylation signaling mediated via a ROS-phosphatase axis. Future studies aiming to link signaling and metabolism will be able to harness these findings to gain further insight into cancer metabolism and potential therapeutics.


bioRxiv | 2018

Panoramic stitching of heterogeneous single-cell transcriptomic data

Brian L Hie; Bryan D. Bryson; Bonnie Berger

Researchers are generating single-cell RNA sequencing (scRNA-seq) profiles of diverse biological systems1–4 and every cell type in the human body.5 Leveraging this data to gain unprecedented insight into biology and disease will require assembling heterogeneous cell populations across multiple experiments, laboratories, and technologies. Although methods for scRNA-seq data integration exist6,7, they often naively merge data sets together even when the data sets have no cell types in common, leading to results that do not correspond to real biological patterns. Here we present Scanorama, inspired by algorithms for panorama stitching, that overcomes the limitations of existing methods to enable accurate, heterogeneous scRNA-seq data set integration. Our strategy identifies and merges the shared cell types among all pairs of data sets and is orders of magnitude faster than existing techniques. We use Scanorama to combine 105,476 cells from 26 diverse scRNA-seq experiments across 9 different technologies into a single comprehensive reference, demonstrating how Scanorama can be used to obtain a more complete picture of cellular function across a wide range of scRNA-seq experiments.

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Forest M. White

Massachusetts Institute of Technology

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Amanda M. Del Rosario

Massachusetts Institute of Technology

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Hannah Johnson

Massachusetts Institute of Technology

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Michael B. Yaffe

Massachusetts Institute of Technology

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Amanda Maffa

Massachusetts Institute of Technology

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Benjamin Aaron Greenberger

Massachusetts Institute of Technology

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Bonnie Berger

Massachusetts Institute of Technology

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Brian L Hie

Massachusetts Institute of Technology

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