Derek Thibault | Boston College (original) (raw)

Papers by Derek Thibault

The type B Arabidopsis Response Regulators (ARRs) of Arabidopsis thaliana are transcription facto... more The type B Arabidopsis Response Regulators (ARRs) of Arabidopsis thaliana are transcription factors that act as positive regulators in the two-component cytokinin signaling pathway. We employed a mutant-based approach to perform a detailed characterization of the roles of ARR1, ARR10, and ARR12 in plant growth and development. The most pronounced phenotype was found in the arr1-3 arr10-5 arr12-1 triple loss-of-function mutant, which showed almost complete insensitivity to high levels of exogenously applied cytokinins. The triple mutant exhibited reduced stature due to decreased cell division in the shoot, enhanced seed size, increased sensitivity to light, altered chlorophyll and anthocyanin concentrations, and an aborted primary root with protoxylem but no metaxylem. Microarray analysis revealed that expression of the majority of cytokinin-regulated genes requires the function of ARR1, ARR10, and ARR12. Characterization of double mutants revealed differing contributions of the type B ARRs to mutant phenotypes. Our results support a model in which cytokinin regulates a wide array of downstream responses through the action of a multistep phosphorelay that culminates in transcriptional regulation by ARR1, ARR10, and ARR12.

Background-Genome-wide association studies have yet to identify the majority of genetic variants ... more Background-Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing.

Hedgehog Interacting Protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD... more Hedgehog Interacting Protein (HHIP) was implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS). However, it remains unclear how HHIP contributes to COPD pathogenesis. To identify genes regulated by HHIP, we performed gene

Recent advances in genetics have spurred rapid progress towards the systematic identification of ... more Recent advances in genetics have spurred rapid progress towards the systematic identification of genes involved in complex diseases. Still, the detailed understanding of the molecular and physiological mechanisms through which these genes affect disease phenotypes remains a major challenge. Here, we identify the asthma disease module, i.e. the local neighborhood of the interactome whose perturbation is associated with asthma, and validate it for functional and pathophysiological relevance, using both computational and experimental approaches. We find that the asthma disease module is enriched with modest GWAS P-values against the background of random variation, and with differentially expressed genes from normal and asthmatic fibroblast cells treated with an asthma-specific drug. The asthma module also contains immune response mechanisms that are shared with other immune-related disease modules. Further, using diverse omics (genomics, † These authors contributed equally to this work. 3005 gene-expression, drug response) data, we identify the GAB1 signaling pathway as an important novel modulator in asthma. The wiring diagram of the uncovered asthma module suggests a relatively close link between GAB1 and glucocorticoids (GCs), which we experimentally validate, observing an increase in the level of GAB1 after GC treatment in BEAS-2B bronchial epithelial cells. The siRNA knockdown of GAB1 in the BEAS-2B cell line resulted in a decrease in the NFkB level, suggesting a novel regulatory path of the pro-inflammatory factor NFkB by GAB1 in asthma.

Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHI... more Multiple intergenic single-nucleotide polymorphisms (SNPs) near hedgehog interacting protein (HHIP) on chromosome 4q31 have been strongly associated with pulmonary function levels and moderate-to-severe chronic obstructive pulmonary disease (COPD). However, whether the effects of variants in this region are related to HHIP or another gene has not been proven. We confirmed genetic association of SNPs in the 4q31 COPD genome-wide association study (GWAS) region in a Polish cohort containing severe COPD cases and healthy smoking controls (P 5 0.001 to 0.002). We found that HHIP expression at both mRNA and protein levels is reduced in COPD lung tissues. We identified a genomic region located ∼85 kb upstream of HHIP which contains a subset of associated SNPs, interacts with the HHIP promoter through a chromatin loop and functions as an HHIP enhancer. The COPD risk haplotype of two SNPs within this enhancer region (rs6537296A and rs1542725C) was associated with statistically significant reductions in HHIP promoter activity. Moreover, rs1542725 demonstrates differential binding to the transcription factor Sp3; the COPD-associated allele exhibits increased Sp3 binding, which is consistent with Sp3's usual function as a transcriptional repressor. Thus, increased Sp3 binding at a functional SNP within the chromosome 4q31 COPD GWAS locus leads to reduced HHIP expression and increased susceptibility to COPD through distal transcriptional regulation. Together, our findings reveal one mechanism through which SNPs upstream of the HHIP gene modulate the expression of HHIP and functionally implicate reduced HHIP gene expression in the pathogenesis of COPD.

Background: Ethylene plays critical roles in plant growth and development, including the regulati... more Background: Ethylene plays critical roles in plant growth and development, including the regulation of cell expansion, senescence, and the response to biotic and abiotic stresses. Elements of the initial signal transduction pathway have been determined, but we are still defining regulatory mechanisms by which the sensitivity of plants to ethylene is modulated. Results: We report here that members of the ARGOS gene family of Arabidopsis, previously implicated in the regulation of plant growth and biomass, function as negative feedback regulators of ethylene signaling. Expression of all four members of the ARGOS family is induced by ethylene, but this induction is blocked in ethylene-insensitive mutants. The dose dependence for ethylene induction varies among the ARGOS family members, suggesting that they could modulate responses across a range of ethylene concentrations. GFP-fusions of ARGOS and ARL localize to the endoplasmic reticulum, the same subcellular location as the ethylene receptors and other initial components of the ethylene signaling pathway. Seedlings with increased expression of ARGOS family members exhibit reduced ethylene sensitivity based on physiological and molecular responses. Conclusions: These results support a model in which the ARGOS gene family functions as part of a negative feedback circuit to desensitize the plant to ethylene, thereby expanding the range of ethylene concentrations to which the plant can respond. These results also indicate that the effects of the ARGOS gene family on plant growth and biomass are mediated through effects on ethylene signal transduction.

Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HI... more Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HIV peripheral neuropathy. We have shown that accumulation of recently recruited (bromodeoxyuridine þ MAC387 þ) monocytes is associated with severe DRG pathology and loss of intraepidermal nerve fibers in SIV-infected macaques. Herein, we blocked leukocyte traffic by treating animals with natalizumab, which binds to a4-integrins. SIV-infected CD8-depleted macaques treated with nata-lizumab either early (the day of infection) or late (28 days after infection) were compared with untreated SIV-infected animals sacrificed at similar times. Histopathology showed diminished DRG pathology with natalizumab treatment, including decreased inflammation, neuronophagia, and Nageotte nodules. Natalizumab treatment resulted in a decrease in the number of bromodeoxyuridine þ (early), MAC387 þ (late), CD68 þ (early and late), and SIVp28 þ (late) macro-phages in DRG tissues. The number of CD3 þ T lymphocytes in DRGs was not affected by natalizumab treatment. Vascular cell adhesion molecule 1, an adhesion molecule that mediates leukocyte traffic, was diminished in DRGs of all natalizumab-treated animals. These data show that blocking monocyte, but not T lymphocyte, traffic to the DRG results in decreased inflammation and pathology, supporting a role for monocyte traffic and activation in HIV peripheral neuropathy. (Am J Pathol 2016, 186: 1754e1761; http://dx.doi.org/10.1016/j.ajpath.2016.03.007) The primary mechanisms of HIV peripheral neuropathy include immune damage secondary to viral infection and mitochondrial toxicity from the antiretrovirals. Because HIV and SIV do not productively infect neurons or Schwann cells, damage to the dorsal root ganglia (DRG) in peripheral neuropathy is believed to be, in part, because of infected and activated macrophages. In vitro and in vivo studies suggest that both viral proteins and systemic inflammation secondary to the viral infection may damage neurons and axons. 1 Using a CD8-depleted SIV-infected rhesus macaque model of peripheral neuropathy, we have shown that accumulation of recruited [bromodeoxyuridine (BrdU) þ MAC387 þ ] monocytes/macrophages was associated with severe DRG pathology. 2 The number of BrdU þ mono-cytes correlated with DRG histopathology, which included neuronophagia, satellitosis, and Nageotte nodules. 2 Our data demonstrate that newly recruited MAC387 þ BrdU þ macro-phages play a significant role in DRG pathogenesis.