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1.  Extensive Rewiring and Complex Evolutionary Dynamics in a C. elegans Multiparameter Transcription Factor Network 
Molecular cell  2013;51(1):116-127.
Gene duplication results in two identical paralogs that diverge through mutation, leading to loss or gain of interactions with other biomolecules. Here, we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks. Remarkably, we find that even highly similar TFs often have different interaction degree and partners. In addition, we find that most TF families have a member that is highly connected in multiple networks. Further, different TF families have opposing correlations between network connectivity and phylogenetic age, suggesting that they are subject to different evolutionary pressures. Finally, TFs that have similar partners in one network generally do not in another, indicating a lack of pressure to retain cross-network similarity. Our multiparameter analyses provide an unprecedented glimpse into the evolutionary dynamics that shaped TF networks.
PMCID: PMC3794439  PMID: 23791784
2.  Regulation of GAD65 expression by SMAR1 and p53 upon Streptozotocin treatment 
BMC Molecular Biology  2012;13:28.
GAD65 (Glutamic acid decarboxylase 65 KDa isoform) is one of the most important auto-antigens involved in Type 1 diabetes induction. Although it serves as one of the first injury markers of β-islets, the mechanisms governing GAD65 expression remain poorly understood. Since the regulation of GAD65 is crucial for the proper functioning of insulin secreting cells, we investigated the stress induced regulation of GAD65 transcription.
The present study shows that SMAR1 regulates GAD65 expression at the transcription level. Using a novel protein-DNA pull-down assay, we show that SMAR1 binding is very specific to GAD65 promoter but not to the other isoform, GAD67. We show that Streptozotocin (STZ) mediated DNA damage leads to upregulation of SMAR1 and p53 expression, resulting in elevated levels of GAD65, in both cell lines as well as mouse β-islets. SMAR1 and p53 act synergistically to up-regulate GAD65 expression upon STZ treatment.
We propose a novel mechanism of GAD65 regulation by synergistic activities of SMAR1 and p53.
PMCID: PMC3459802  PMID: 22978699
SMAR1; Diabetes; GAD65; p53; Streptozotocin
3.  Enhanced yeast one-hybrid (eY1H) assays for high-throughput gene-centered regulatory network mapping 
Nature Methods  2011;8(12):1059-1064.
A major challenge in systems biology is to understand the gene regulatory networks that drive development, physiology and pathology. Interactions between transcription factors and regulatory genomic regions provide the first level of gene control. Gateway-compatible yeast one-hybrid (Y1H) assays present a convenient method to identify and characterize the repertoire of transcription factors that can bind a DNA sequence of interest. To delineate genome-scale regulatory networks, however, large sets of DNA fragments need to be processed at high throughput and high coverage. Here, we present “enhanced” Y1H (eY1H) assays that utilize a robotic mating platform with a set of improved Y1H reagents and automated readout quantification. We demonstrate that eY1H assays provide excellent coverage and identify interacting transcription factors for multiple DNA fragments in a short amount of time. eY1H assays will be an important tool for gene regulatory network mapping in Caenorhabditis elegans and other model organisms, as well as humans.
PMCID: PMC3235803  PMID: 22037705

Results 1-3 (3)