Diploid cells of Saccharomyces sporulate when starved of nitrogen and fermentable carbon source. These nutritional signals converge on to the upstream regulatory region of IME1 gene. Ime1p interacts with Ume6p, a general repressor of sporulation-specific genes during mitotic growth and the complex activates the transcription of IME2 and other early meiotic genes unleashing a cascade of gene regulatory events that lead to initiation of pre-meiotic DNA replication, meiotic recombination, meiotic divisions and subsequently spore maturation.
A gene list comprising of approximately 1800 genes identified by microarray expression profiling studies to be involved in early sporulation and additional genes shown to have a sporulation phenotype upon deletion was used to derive a putative network underlying the poorly understood developmental pathway of sporulation. The resulting network with 1461 genes and 5247 interactions can be further filtered using querying utilities to selectively view the DNA-protein interactions or protein-protein interactions, various known functional modules operating during sporulation such as DNA replication/recombination/repair, Peptidolysis and proteolysis, Cell cycle regulation, regulation of transcription from Pol II promoter, ribosome complexes, etc.
GO Biological Process annotations show that several of tanscription factors are involved in regulation of glucose repression, starvation response to various nutrients, physiological stress response and cellular processes such as autophagy. This information can further be used to create hypothesis-based wet-lab experiments involving deletion of the specific binding site for each of these transcriptional regulators and monitoring the effect on IME1 transcription in response to the corresponding environmental condition.
In this project we describe data integration, analysis and management environment for systems biology research for studying host-pathogen interaction. We developed methods and tools for simplifying and streamlining the process of integration of diverse experimental data types, including molecular interaction, gene expression levels, genomic sequences, protein structure information, phylogenetic classification, and virulence data for pathogen-related studies. Specifically, systems level studies on Influenza viruses identified host molecular pathways that appear to be induced or repressed during infection, and these results highlight pathways exhibiting responses specific for a given pathogen infection. These results demonstrate the usefulness of dynamic data integration techniques, and enable a hypothesis generation platform for major human disease systems. In this integrated database we provide access to heterogeneous information that are of value to researchers in epidemiology, virology and vaccine development.
We have chosen evolutionary distance, as specified by phylogenetic trees, to rationalize the information integration scheme of this database. The assumption here is that virus properties, such as virulence, infectivity, host-specificity, the ability to jump host species, geographic locations, morbidity in an epidemic, or host-specific reactions are related by evolutionary lineages. RNA and protein sequence data, and phylogenetic trees constructed over these sequences, form the core of this database.
Giardia is a major cause of waterborne intestinal disease and is also of basic biological interest as one of the earliest known eukaryotic organisms, with both prokaryotic and eukaryotic properties. Fran Gillin group’s orientation is unusual because they focus broadly on this organism and are not tied to specific techniques (Ann. Rev. Microbiol. 50: 679-705,1996). They ask cutting edge questions and design creative approaches to achieve incisive answers.
Fran Gillin’s lab has completed the giardial life cycle in vitro for the first time, by inducing the flagellated “trophozoite” form that colonizes the small intestine to differentiate into cysts that survive in cold water. They discovered a novel regulated secretory pathway for the transport of cyst wall proteins during encystation. Cysts infect a new host by responding to signals from the host that lead to a rapid and dramatic differentiation. Excystation entails establishing cellular polarity, cell division, attachment, increases in metabolism, and antigenic switching.
Giardia is also a valuable model for study of the prokaryotic-eukaryotic divergence and we are actively involved in biological aspects of a giardial genome project (PNAS 95:229-234, 1998; Molecular and Biochemical Parasitology, in press).
Current questions of Giardia project include:
- How are giardial genes regulated during differentiation?
- What are the cell signaling pathways in differentiation and pathogenesis?
- How are components of the cyst wall transported and how is this fibrous structure assembled?
- What are the structure and function of the unusual cysteine-rich variant surface protein of Giardia?
- What can Giardial genes and pathways tell us about the evolution of the eukaryotic cell?
- How does Giardia make people sick?
New systems biology and data integration approaches allow the rapid characterization of phylogentically conserved binding sites (promoter structures) that are shared among transcription factors controlling the expression of gene products that act together in the same biological context. Such methods can be used to find novel interacting molecules and explain mechanism of transcriptional regulation.
Here, we demonstrate such principles by applying them to functionally related genes and proteins important in Hypertension.
Genome-wide co-expression analysis together with an evolutionarily conserved promoter model generated a functional molecular network of Hypertension. Functional modular networks of chromogranins, catecholamins and transcription factors crucial for Hypertension effectively identified novel gene targets as well as transcription factors in human tissues. Novel gene targets were sequenced in human tissues and experimentally validated the method.
Preliminary data suggests that in spite of the apparent multi-specific nature of cortex and brain development including numerous events of neuron growth, synapses establishment, connections increase, neurons elimination, etc., there exists gene-dependent and pre-programmed determinants that govern that general cortex development. This raises a possibility that one can elucidate the general mechanisms of gene regulation leading to cortex development and eventually to the brain-mine transition. Read More
In this Driving Project together with Gao Zhang and Meenhard Herlyn group from The Wistar Institute/UPenn we have explored gene expression data of human melanoma cells to investigate the cell transition from the autophagy to senescence. We have explored user’s gene expression experiment together with publically available gene expression data. Read More
COnstraints-Based Reconstruction and Analysis (COBRA) methods that have been successfully employed in the field of microbial metabolic engineering and have begun to be extended to the field of public health is integrated with BiologicalNetworks system to deal with computational hurdles associated with analyzing large metabolic network models.
The extended COBRA/BiologicalNetworks integrated system facilitates visual and computational interpretation of omics data sets in the context of BiGG and IntegromeDB knowledge-bases. The integrated system not only facilitates the extraction of valuable information from the vast sea of available omics data, it also provides an interface that allows biomedical researchers to exploit proven COBRA and BiologicalNetworks methods with minimal effort.
Autism Spectrum disorders (ASD) still do not have unifying etiology. Current studies are showing that mechanisms of ASD are linked to a complex of interconnected epigenetic and genetic factors that change the dynamics of organism development. Our group together with Dr. Tsygelny from UCSD has been involved in the studies of such inter-players responsible for ASD- a pair of proteins neuroligin-neurexin and others.
In this Driving Project genome-wide association studies of more than 400 unrelated ASD patients showing changes in various regions of human chromosomes related to ASD was used to analyze hierarchical clusters of small number of ASD related genes and transcription factors working on each stage of brain development. It was shown that the genetic controls of brain development are significantly different from such controls in other organs development.
Thus, elucidation of possible mechanisms of ASD with recommendation for cures has to be addressed using a multi-level strategy that will show corresponding changes in parameters on different levels during the brain development.
The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) bacterias around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-bacterial agents. Read More
NF-kB plays critical roles in the development of the immune system, in the inflammatory and immune response, and in controlling cell survival and proliferation. As such, it has broad and critical roles in multiple aspects of carcinogenesis and cancer pathogenesis, in determining chemoresistance and cancer progression. Read More