The Gardini Laboratory
The Gardini laboratory is interested in how cells acquire and maintain their transcriptional identity. We examine transcription of coding and noncoding genes by RNA Polymerase II (RNAPII), a process that boasts several layers of regulation: i) transcription factors and chromatin remodelers determine chromatin accessibility and recruitment of the basal transcription machinery; ii) the rate of transcription is controlled by elongation factors such as NELF and pTEFb that act as positive or negative regulators RNA polymerase processivity; iii) distal DNA regulatory elements (enhancers) establish chromatin loops with neighboring genes and modulate gene activation, particularly of developmentally regulated genes.
The lab studies how all these regulatory layers contribute to coordinating gene expression during cell differentiation and oncogenesis.
Elisa Barbieri, Ph.D.
Marco Trizzino, Ph.D.
There are three major lines of research in the lab:
Role of enhancer and enhancer-derived noncoding RNAs during normal hematopoiesis and leukemia
Enhancers are distal regulatory elements scattered throughout the entire genome. They play a fundamental role in orchestrating gene regulation during critical developmental processes such as cell differentiation. Enhancers were recently discovered to be active spots for transcription of long noncoding RNAs (eRNAs). These short-lived, non-polyadenylated transcripts are required to establish communication between the promoter and the distant regulatory enhancer by creating DNA “loops”, resulting in expression of the target protein-coding gene. The underlying mechanisms are poorly understood and the potential contribution of enhancers and eRNAs to cancer just started to emerge. The lab is keen to understand how a network of enhancers drive the physiological process of hematopoiesis, and how is this network disrupted during leukemogenesis.
Transcriptional activation mediated by eRNAs
Functional dissection of the Integrator protein complex
Integrator is a large, evolutionarily conserved, multiprotein complex that regulates several transcriptional processes. For instance, Integrator controls pause-release of RNAPII at several promoters. In addition, Integrator regulates enhancer function through the processing of noncoding eRNAs. In the lab, we integrate genome-wide techniques, such as ChIP-seq, RNA-seq, ATAC-seq and Global Run-On Sequencing (GRO-seq), together with large-scale affinity purification, and investigate the function of the Integrator complex in cell differentiation.
Role of chromatin remodelers in ovarian cancer
Chromatin remodelers regulate DNA accessibility by positioning nucleosomes at active promoters and enhancers. In the lab, we investigate the function of SWI/SNF, the most mutated chromatin remodeler in all human cancers, with an emphasis on epithelial ovarian tumors. Subunits of SWI/SNF, such as ARID1A, are found mutated in sporadic ovarian tumors and their specific contribution to SWI/SNF activity is poorly understood.
Dmitry I. Gabrilovich, M.D., Ph.D.
Christopher M. Davis Professor
Professor & Program Leader, Immunology, Microenvironment & Metastasis Program