UB’s New York State Center of Excellence in Bioinformatics & Life Sciences (CBLS) is home to over 250 scientists and research staff with biological, physical and computational expertise, all of whom are engaged in interdisciplinary biomedical research with collaborators from across the region, the country and the globe. CBLS faculty members are affiliated with our primary research partners, including the University at Buffalo, Roswell Park Cancer Institute, and the Hauptmann-Woodward Medical Research Institute.
Apoptosis and cell death; Bioinformatics; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Regulation of metabolism
My laboratory studies the cell-autonomous and non-cell-autonomous mechanisms of axon degeneration, a process akin to programmed cell death. In other words, we are attempting to elucidate what causes axon breakdown from within neurons and which external (glial) events trigger axon loss. Degeneration of axons is a hallmark in many neurodegenerative conditions, including those associated with abnormal glia. We have great hope that understanding why and how axons degenerate may lead to more efficient neuroprotective therapies tailored specifically to support axons and their surrounding glia. Axons are the longest cellular projections of neurons relaying electrical and biochemical signals in nerves and white-matter tracts of the nervous system. As such, they are critical for neuronal wiring and transport of neuronal maintenance signals. Because of their incredible length and energetic demand (human motor neurons can be one meter long), however, axons are very vulnerable and at continuous risk of damage. Axons do not exist in isolation but are inextricably and intimately associated with their enwrapping glia (Schwann cells and oligodendrocytes) to form a unique axon-glia unit. The most relevant neurological symptoms in a number of debilitating neurodegenerative conditions are due to compromised axon integrity. Thus, neuroprotective therapies promoting axon stability have great potential for more effective treatment. Recent studies indicate that axonal degeneration, at least in experimental settings, is an active and highly regulated process akin to programmed cell death (‘axonal auto-destruction’). Moreover, it is increasingly realized that axonal maintenance relies not only on neuron-derived provisions but also on trophic support from their enwrapping glia. The mechanism for this non-cell-autonomous support function remains unknown, but emerging evidence indicates that it is distinct from the glial role in insulating axons with myelin. We are pursuing the intriguing question of whether abolished support by aberrant delivery of metabolites and other trophic factors from glia into axons is mechanistically linked to the induction of axonal auto-destruction. This concept is supported by our recent finding that metabolic dysregulation exclusively in Schwann cells is sufficient to trigger axon breakdown.
Bioinformatics; Genomics and proteomics; Molecular and Cellular Biology; Molecular genetics; Gene Expression; Transcription and Translation
Our research group is interested in how regulatory proteins are targeted to the correct DNA binding sites at the correct time. Transcription factors are directed to their genomic targets by DNA sequence, local chromatin structure, and protein-protein interactions. These modulators of transcription factor binding are not independent but function both cooperatively and competitively to regulate where transcription factors bind. Understanding how these modulators affect transcription factor binding in vivo remains a major unsolved biological problem. We use the model organism Saccharomyces cerevisiae to address the disconnect between the presence of the correct DNA binding sequence and true regulatory protein binding, integrating both experimental and computational approaches to: i) investigate transcription factor binding in response to environmental stress, ii) identify and characterize the mechanisms directing transcription factor target selection, and iii) and develop bioinformatics tools to analyze and interpret ChIP-seq experiments and chromatin structural patterns.
Neurology; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Signal Transduction; Inherited Metabolic Disorders; Transgenic organisms
My laboratory seeks to understand the molecular basis of myelination and myelin diseases. Myelin is a multi-lamellar sheath that invests large axons and permits rapid conduction of nerve signals. Failure in myelin synthesis and myelin breakdown cause several important neurological diseases, including multiple sclerosis, leukodystrophies and peripheral dysmyelinating neuropathies. In some of these diseases, genetic mutations cause defects in cytoskeletal, adhesion and signaling molecules. I work with a team of undergraduate and graduate students, postdoctoral fellows, technicians, senior scientists and many international collaborators to discover how these molecules normally coordinate cell-cell and cell-extracellular matrix interactions to generate the cytoarchitecture of myelinated axons. We use a variety of approaches, including generation of mice carrying genetic abnormalities, cultures of myelinating glia and neurons, imaging, biochemistry and morphology to understand the role of these molecules in normal and pathological development. By comparing normal myelination to the abnormalities occurring in human diseases, we aim to identify molecular mechanisms that pharmacological intervention might correct. For example, we described how the protein dystroglycan associates with different proteins, some of which impact human neuropathies, depending on a proteolitic cleavage that can be regulated to improve the disease. Similarly, we found that molecules such as integrins and RhoGTPAses are required for glia to extend large processes that will become myelin around axons. In certain neuromuscular disorders, defective signaling pathways that converge on these molecules cause failure to produce or mantain an healthy myelin Finally, in collaborations with scientists and clinicians in the Hunter J. Kelly Research Institute, we are generating transgenic forms of GalC, an enzyme deficient in Krabbe leukodystrophy, to investigate which cells requires the enzyme. Investigating how GalC is handled may help find a cure for this devastating disease.
Bioinformatics; Cell growth, differentiation and development; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Gene Expression; Stem Cells; Transgenic organisms
My research goal is to gain a better understanding of how proteins that interact with DNA regulate RNA transcription, DNA replication and metazoan development. I mentor undergraduate and graduate students in my lab; we focus on the structure and function of the Nuclear Factor I (NFI) family of site-specific DNA binding proteins, and we are investigating their roles in development. Our work has been made possible by our development of loss-of-function mutations of the NFI genes in the mouse and C. elegans. We are addressing four major questions in my laboratory and in collaboration with a number of talented collaborators: What is the structure of the NFI DNA-binding domain? How does NFI recognize and interact with DNA? Does NFI change the structure of DNA when it binds? What proteins interact with NFI to stimulate RNA transcription and/or DNA replication? These research questions are explored in my lab through two major projects focused on the role of NFIB in lung development and the role of NFIX in brain development. When NFIB is deleted from the germline of mice the animals die at birth because their lungs fail to mature normally. This provides a good model for the problems that occur with premature infants, whose lungs also fail to mature normally. We are using this model to determine how NFIB promotes lung maturation with the goal of being able to stimulate this process in premature infants. In our NFIX knockout animals, the brains of the animals are actually larger than normal and contain large numbers of cells in an area known to be the site of postnatal neurogenesis. We have evidence that NFIX may regulate the proliferation and differentiation of neural stem cells, which produce new neurons throughout adult life. Our aim is to understand the specific target genes that NFIX regulates in the adult brain to control this process of neurogenesis.
Bioinformatics; Cell growth, differentiation and development; Gene Expression; Genomics and proteomics; Molecular genetics; Signal Transduction
Research in my laboratory investigates the genetic regulatory circuitry that controls how cell fates are determined during development. We focus on two key aspects, intercellular signaling and transcriptional regulation, using primarily the fruit fly Drosophila melanogaster due to its extremely well-annotated genome and amenability to experimental manipulation. All conclusions, however, are expected to relate directly to mammalian (including human) gene regulation. Recently, we have also started investigating the regulatory genomics of other insect species of both medical and agricultural importance, beginning with the development of methods for regulatory element discovery in species with fully sequenced genomes but little functional, experimental data. A defining feature of my laboratory is that it takes both wet-lab and computational/bioinformatics approaches to studying the same set of problems about development and transcriptional regulation; hypotheses and ideas generated using one set of methods are tested and explored using the other. Current research in the laboratory falls into two main areas: 1) discovery and characterization of transcriptional cis-regulatory modules (CRMs), and 2) mechanisms of specificity for receptor tyrosine kinase (RTK) signaling. The combined results of these studies will provide insight into gene regulation, genome structure, intercellular signaling, and the regulatory networks that govern embryonic development. My group is also heavily involved in biocuration through our development and maintenance of REDfly, an internationally-recognized curated database of known Drosophila transcriptional cis-regulatory modules (CRMs) and transcription factor binding sites (TFBSs). Despite more than 25 years of experimental determination of these elements, the data have never been collected into a single searchable database. REDfly seeks to include all experimentally verified fly regulatory elements along with their DNA sequence, their associated genes, and the expression patterns they direct. REDfly is by far the most comprehensive database of regulatory elements for the higher eukaryotes and serves as an important resource for the fly and bioinformatics communities.
Bioinformatics; Gene Expression; Genomics and proteomics
My research is focused on developing bioinformatics algorithms especially through sequencing analysis and data integration, to understand better transcriptional and epigenetic regulation. Transcription factor often binds to DNA and interferes with transcription machinery to enhance or repress gene expression. Epigenetic features such as histone modification, chromatin remodeling factor binding, DNA methylation, and chromatin 3D organization add yet another layer of information, making it more complex to understand the regulation dynamics within the nucleus. With advancing sequencing technology, however, such information now can be measured and quantified in genome scale, though the growing number of big genomic datasets creates challenges as well as opportunities for bioinformatics methodologies. The focus of our lab is to build algorithms, analysis platforms and databases to integrate big datasets from the public domain into various biological questions and disease models. The MACS (Genome Biology 2008) algorithm, on which I worked to develop, is one of the most widely-used algorithms for predicting cis-regulatory elements from Chromatin Immunoprecipitation with high-throughput sequencing (ChIP-seq). The algorithm has been evolving over years to accommodate various factor types from punctuate transcription factor binding to long-range histone modifications. It has been used to process hundreds of publicly-available datasets in the mod/ENCODE project, and it continues as a focus of my lab. I also worked to build an integrative platform for ChIP analysis based on Galaxy framework, named Cistrome (Genome Biology 2011). This platform provides both a user-friendly interface and rich functionality for biologists to manage and process their high-throughput genomic data and to publish the results conveniently over the Internet. The Cistrome platform will continue as a collaborative project between my UB lab and research partners at Harvard University. I have also been involved in many collaborative research projects, such as circadian binding of histone deacetylase and nuclear receptor Rev-Erba in mouse liver (Science 2011), and the modENCODE consortium project to elucidate chromatin factor functions of C. elegans (Genome Research 2011 and Science 2010).
Bioinformatics; Cell growth, differentiation and development; Neurobiology
My laboratory seeks to understand the transcriptional regulatory network governing the differentiation of oligodendrocytes and central nervous system (CNS) myelination, with the long-term goal of translating this knowledge into the treatment of demyelinating diseases. CNS myelination by oligodendrocytes is important not only for saltatory conduction of action potentials but also for trophic support of nerve axons. An improved understanding of how the differentiation of oligodendrocytes is regulated for CNS myelination should provide a firm basis on which to develop more effective therapeutics for demyelinating diseases. Toward this goal, we are currently pursuing two different research directions. The first is to elucidate the functional mechanism of Myrf, a key transcription factor for CNS myelination. Conditional knockout mice in which Myrf is knocked out in the oligodendrocyte lineage cells completely fail to develop CNS myelin and exhibit severe neurological symptoms, eventually prematurely dying. Recently, we and the Emery laboratory have independently made the surprising discovery that Myrf is generated as an integral membrane protein that is auto-cleaved by its ICA domain into two fragments. This discovery invokes a number of fundamental questions about how Myrf drives the differentiation of oligodendrocytes for CNS myelination. We employ both computational and experimental laboratory methodologies to elucidate the functional mechanism of Myrf. The second direction is to identify new transcription factors for CNS myelination. By taking advantage of our computational expertise, we have performed integrated computational analysis of functional genomics data that are publicly available to predict a number of new transcription factors for oligodendrocyte differentiation. We are currently characterizing them using primary oligodendrocyte cultures. Promising hits will be further analyzed by generating knockout mice to test for in vivo relevance.
Genomics and proteomics; Molecular and Cellular Biology; Gene Expression
My laboratory is interested in understanding the transcriptional control mechanisms that dictate epithelial cell development and differentiation. Specifically, we seek to understand the functional role of a p53-family member, p63 and Ets family of proteins in epithelial cells such as those of the skin and mammary glands. Towards this end, we have developed and characterized transgenic mice in which the normal expression pattern of these crucial factors is altered by both gain-of-function (Tet-inducible transgenic system) and loss-of-function (knockout) experiments. Our broad objectives are to elucidate the molecular mechanism by which transcription factors such as p63 and Ets proteins regulate their target genes and how such regulation of specific pathways dictate cell fate, development and differentiation. We utilize broad biochemical and genetic approaches, cell culture systems and state of the art genome-wide interrogation techniques to answer questions about differentiation of progenitor/stem populations and to examine molecular consequences of altered expression of transcription factors. These studies will not only help better understand the normal physiological processes but also lead to novel mechanistic insights into the pathophysiology of wide range of disease including cancer.