Assistant Professor, Biodesign Virginia G. Piper Center for Personalized Diagnostics
Associate Faculty, Biodesign Center for Mechanisms of Evolution
My scientific path has taken me from bioinformatics to wet-bench biology to high-throughput genomic projects. In spring 1999, after I graduated from the University La Sapienza in Rome (Italy), I joined Dr. Lincoln Stein’s lab at Cold Spring Harbor Laboratory (CSHL), NY, as a Scientific Programmer to learn bioinformatics. Lincoln is a pioneer in the field and well-known for developing complex genomic interfaces and tools that make the access and analysis of genomic datasets simple for non-expert users. At that time he was involved with the SNP consortium, a multi-country initiative to identify and catalog genetic similarities and differences between human beings. The project used the BLAST algorithm to search for single mismatches between DNA sequences recovered from patients. The human genome was not sequenced at the time, and my task was to develop Perl software to extract human gene records from the NCBI server and create a target database to map SNPs in the human genome. It was in Lincoln’s laboratory that I learned about C. elegans and its biology. It was the only fully sequenced multicellular organism at the time, and Lincoln was involved in the preparation of the worm public repository, the now well-established C. elegans database WormBase (www.wormbase.org), together with Richard Durbin (now at the Sanger Center, UK), Jean Thierry-Mieg at NCBI and Paul Sternberg at Caltech. I was the lead programmer during the early stages of the database and supervised several of the database releases. Much of the Perl code I wrote more than 10 years ago still powers WormBase, and is now part of the widely used gBrowse, a combination of database and interactive web pages used for manipulating and displaying annotations of genomes.
In 2000, I started my Ph.D. at the Watson School of Biological Sciences (WSBS) at Cold Spring Harbor Laboratory (CSHL), where I joined Dr. Winship Herr’s laboratory. Winship, who was the assistant director of CSHL and the founding Dean of the WSBS at that time, is interested in transcription initiation. In Winship's lab I became interested in how the basic transcription machinery recognizes promoters and produces mRNAs. My research focused on the study of a 500 amino acid region termed ‘Basic region’ in the human transcriptional co-activator Host Cell Factor 1 (HCF-1), which he cloned 20 years ago. The Basic region is involved in sustaining cell proliferation in several metazoans including humans, but the mechanisms are unknown. I performed comprehensive genetic analyses in hamster and human cells trying to identify the elements in the HCF-1 Basic region, which are required for sustaining cell proliferation. I further characterized selected known HCF-1 interacting proteins and their involvement in the cell proliferation effect driven by HCF-1 using immunofluorescence and co-immunoprecipitation experiments. Surprisingly, much like the transcriptional activation domains of sequence-specific DNA-binding transcription factors, my work showed that there is no unique sequence within the Basic region required for promoting cell proliferation or G1-to-S phase transition. Actually, the ability to promote these activities is size-dependent, such that the shorter the Basic region segment, the less activity is observed. The Basic region displays considerable structural plasticity since each half is able to promote cell proliferation when duplicated in tandem. Consistent with a potential role in promoting cell cycle progression, I showed using co-immunoprecipitation assays that the Sin3a HDAC component can associate independently with either multiple region of HCF-1, suggesting a potential connection between these two factors.
For my post-doctoral work, I joined Dr. Fabio Piano’s laboratory in the Department of Genomics and Systems Biology at New York University in spring 2006. I met Fabio when I was still in Lincoln's laboratory and he was a post-doctoral fellow in Dr. Kemphues laboratory at Cornell University. Fabio performed one of the early genetic screens searching for genes required in early C. elegans embryogenesis. He came to Lincoln for help with the bioinformatics pipeline needed to analyze his data, and our collaboration resulted in a publication. During that summer of 1999, Fabio introduced me to RNA interference, which was just inadvertently discovered in his advisor’s lab a few years before and would soon explode into its own field within a few years.
In Fabio’s lab I was able to apply both my computational and wet-bench skills, resulting in the publication of two coauthor first-author papers. We were part of a collaborative effort led by the NHGRI and funded by the modENCODE consortium, which aims to highlight functional elements in the genomes of C. elegans and D. melanogaster. Fabio asked me to lead the 3’UTRome project in his laboratory, where I developed and performed the cloning and bioinformatics pipeline that produced a cDNA library of 3’UTR sequences for ~20,000 unique transcripts of the soil nematode C. elegans. The library is a milestone for 3’UTR biology, and provides the foundation for future studies of these poorly understood genomic regions. I cloned all 3’UTRs from the C. elegans transcriptome, sequenced them using Sanger and Next-Gen platforms, and contributed to the annotation of thousands of 3’UTR isoforms. My data are distributed on an ongoing basis through the modENCODE website (http://www.modencode.org), WormBase - the C. elegans genomic repository which I previously co-developed in Dr. Lincoln Stein’s Laboratory at CSHL, and the database UTRome.org (http://www.utrome.org) which I developed and is one of the official release servers for the project. In addition, I developed several tools to test my cloned 3’UTRs in downstream analyses in worms.
In August 2011, I accepted a faculty position at Arizona State University and setup my laboratory in the Biodesign Institute, where I conduct my research studying post-transcriptional gene regulation.