Cell Biology, Neurobiology & Anatomy

Education:
PhD, University of Illinois at Chicago, 1996
Postdoctoral, Brown University and Fox Chase Cancer Center

Graduate Program:
Program in Cell and Developmental Biology

Research Area: Molecular mechanisms underlying liver development and function, with a particular focus on the role played by
chromatin structure in the transcriptional regulation of liver genes
 

Positions Available:
Positions are currently available for Postdoctoral Fellows. Please contact Dr. Lisa Cirillo at lcirillo@mcw.edu
or visit our Postdoctoral Positions web page. 

Our laboratory seeks to understand the fundamental mechanisms which underlie the complex patterns of gene expression required for appropriate liver development and function. Transcription in eukaryotes occurs in the context of chromatin. DNA in the nucleus is packaged into chromatin, the basic subunit of which is a nucleosome consisting of DNA wrapped around an octamer of core histone proteins. Nucleosomes are, in turn, folded and compacted through the binding of the linker histone and other chromatin binding proteins, into higher-order structures. This packaging of DNA into the chromatin fiber constrains transcription factor binding and gene activation. Our primary research objective is to understand the mechanisms used by transcription factors to gain access and bind to their sites at promoters and enhancers in silent compacted chromatin, and, once bound, to remodel chromatin structure as a prerequisite to activating gene expression.

The first regulatory factors to bind a gene are the most likely to play a key role in activating genes in silent compacted chromatin. Two liver-enriched regulatory factors, the winged-helix transcription factor FoxA1 (formerly HNF3), and GATA-4, a member of the GATA family of zinc-finger DNA binding proteins, are the earliest known regulatory factors to bind the enhancer of the serum albumin gene, in the liver precursor cells of the early mouse embryo. Previous studies have demonstrated that FoxA1 and GATA-4, but not other proteins which bind to the albumin enhancer at later developmental time points, are able to bind to their sites in compacted chromatin at the albumin enhancer in vitro, and open the local nucleosomal domain (Cirillo et al, 2002). This chromatin opening, surprisingly, does not require ATP-dependent chromatin remodeling enzymes and does not occur in the absence of the linker histone. These studies suggest a model for albumin enhancer activation by FoxA1 and GATA-4, through chromatin opening, indicating that early or “pioneer” developmental transcription factors are intrinsically capable of initiating chromatin opening events. Ongoing research projects in the laboratory utilize in vivo knock-in, knock-down, and chromatin mapping strategies in combination with in vitro chromatin reconstitution to examine and compare the mechanisms used by FoxA1 and GATA-4 to regulate the chromatin remodeling events required for transcription of the albumin and other liver genes and 2) the role played by the linker histone in gene activation events. These studies should add to our understanding of developmental gene activation as well as provide much needed insight into the mechanisms through which linker histone acts to facilitate transcription in a gene specific manner.

The chromatin binding and remodeling capabilities of FoxA1 are mediated in large part through its winged-helix DNA binding domain, also known as the forkhead box. Crystallography has shown that this DNA binding domain, which is highly conserved among other members of the forkhead (Fox) family of transcription factors, of which FoxA1 is a member, is structurally similar to that used by the linker histone to bind to and compact chromatin. It has therefore been suggested that other forkhead factors might mediate their effects on cellular processes through chromatin modification. We have recently extended our studies of chromatin structure and function during liver development to encompass forkhead factors (members of the FoxO subfamily) with demonstrated roles in insulin signaling, with specific focus on transcriptional regulation of the IGFBP-1 and glucose-6-phosphatase genes in hepatocytes. New data suggests that FoxO factors, much like FoxA1, function through chromatin remodeling (Hatta and Cirillo, 2007). We are currently investigating 1) the role played by FoxO-mediated chromatin remodeling on binding and recruitment events necessary for gene activation and 2) the effect of insulin-mediated posttranslational modification on chromatin binding by FoxO factors. These studies should provide us with a better understanding of the role played by these important regulatory proteins in metabolic processes in the adult liver and improve our insight into the etiology of diabetes and liver cancer.

Top left to right:  Bea Hucke, Yoonyoung Go & Fengjie Liu,
Bottom left to right:  Mitsutoki Hatta, Lisa Cirillo & Sarah Kohler

Selected Publications: