Publications by authors named "Aaron E Lampano"

5 Publications

  • Page 1 of 1

Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

Immunity 2015 Apr;42(4):679-91

Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.
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http://dx.doi.org/10.1016/j.immuni.2015.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407145PMC
April 2015

A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses.

Nature 2012 Oct 16;490(7420):421-5. Epub 2012 Sep 16.

Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.

Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses and their transcription is regulated by a variety of transcription factors; principal among these is the family of interferon regulatory factors (IRFs). The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex interactions that give rise to precise coordination of the interferon response. Here we have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription and we have further demonstrated that FOXO3, IRF7 and IFN-I form a coherent feed-forward regulatory circuit. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.
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http://dx.doi.org/10.1038/nature11428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556990PMC
October 2012

Genome-wide histone acetylation data improve prediction of mammalian transcription factor binding sites.

Bioinformatics 2010 Sep 27;26(17):2071-5. Epub 2010 Jul 27.

Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103, USA.

Motivation: Histone acetylation (HAc) is associated with open chromatin, and HAc has been shown to facilitate transcription factor (TF) binding in mammalian cells. In the innate immune system context, epigenetic studies strongly implicate HAc in the transcriptional response of activated macrophages. We hypothesized that using data from large-scale sequencing of a HAc chromatin immunoprecipitation assay (ChIP-Seq) would improve the performance of computational prediction of binding locations of TFs mediating the response to a signaling event, namely, macrophage activation.

Results: We tested this hypothesis using a multi-evidence approach for predicting binding sites. As a training/test dataset, we used ChIP-Seq-derived TF binding site locations for five TFs in activated murine macrophages. Our model combined TF binding site motif scanning with evidence from sequence-based sources and from HAc ChIP-Seq data, using a weighted sum of thresholded scores. We find that using HAc data significantly improves the performance of motif-based TF binding site prediction. Furthermore, we find that within regions of high HAc, local minima of the HAc ChIP-Seq signal are particularly strongly correlated with TF binding locations. Our model, using motif scanning and HAc local minima, improves the sensitivity for TF binding site prediction by approximately 50% over a model based on motif scanning alone, at a false positive rate cutoff of 0.01.

Availability: The data and software source code for model training and validation are freely available online at http://magnet.systemsbiology.net/hac.
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http://dx.doi.org/10.1093/bioinformatics/btq405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922897PMC
September 2010

Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals.

Nat Immunol 2009 Apr 8;10(4):437-43. Epub 2009 Mar 8.

Institute for Systems Biology, Seattle, Washington, USA.

The innate immune system is like a double-edged sword: it is absolutely required for host defense against infection, but when uncontrolled, it can trigger a plethora of inflammatory diseases. Here we use systems-biology approaches to predict and confirm the existence of a gene-regulatory network involving dynamic interaction among the transcription factors NF-kappaB, C/EBPdelta and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encoding interleukin 6 and C/EBPdelta and experimentally confirmed the prediction that the combination of an initiator (NF-kappaB), an amplifier (C/EBPdelta) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately.
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http://dx.doi.org/10.1038/ni.1721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780024PMC
April 2009

Cutting edge: Tlr5-/- mice are more susceptible to Escherichia coli urinary tract infection.

J Immunol 2007 Apr;178(8):4717-20

Institute for Systems Biology, Seattle, WA 98103, USA.

Although TLR5 regulates the innate immune response to bacterial flagellin, it is unclear whether its function is essential during in vivo murine infections. To examine this question, we challenged Tlr5(-/-) mice transurethrally with Escherichia coli. At 2 days postinfection, wild-type mice exhibited increased inflammation of the bladder in comparison to Tlr5(-/-) mice. By day 5 postinfection, Tlr5(-/-) mice had significantly more bacteria in the bladders and kidneys in comparison to wild-type mice and showed increased inflammation in both organs. In addition, flagellin induced high levels of cytokine and chemokine expression in the bladder that was dependent on TLR5. Together, these data represent the first evidence that TLR5 regulates the innate immune response in the urinary tract and is essential for an effective murine in vivo immune response to an extracellular pathogen.
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http://dx.doi.org/10.4049/jimmunol.178.8.4717DOI Listing
April 2007