Chromosomal DNA is packaged into protein/DNA structures called chromatin. Certain chromatin structures silence genes, but others facilitate gene expression. Chromatin is therefore a remarkably dynamic material.
Structures formed to prevent gene expression can be remodeled to enable expression in response to cellular signals during growth and development. We purify and characterize large protein complexes that remodel and modify chromosome structure to understand their mechanisms, regulation, and targeting.
We are interested in how chromatin structure helps regulate gene transcription and how this process is misregulated in cancer. We address and approach this broad issue in several ways. We purify and characterize large protein complexes that remodel and modify chromosome structure.
We are also interested in epigenetics, and how chromatin structure and DNA methylation/demethylation dynamics are used in germ cells to poise the genome for development and in embryos to guide developmental processes.
Many genes important for cell proliferation and differentiation are regulated at the chromatin level. It’s important to understand how packaging by chromatin influences transcription and to characterize the protein machines that facilitate the transitions between chromatin states. These are the goals of my laboratory.
Nucleosomes: The Basic Units of Chromatin
The basic unit of chromatin structure is the nucleosome, which consists of a "bead" composed of eight histone proteins, around which 147 base pairs of DNA are wrapped.
Nucleosomes display three dynamic properties in vivo:
- compositional changes,
- covalent modifications by enzymes,
- and repositioning.
Nucleosomes can be reconstructed from special histone variants, which specialize nucleosomes in particular regions along the chromosome. These variant nucleosomes assist with biological processes such as centromere construction or gene activation.
Between nucleosomes is a small segment of DNA (about 40 bases), leading to a view of the chromosome that resembles beads on a string. The wrapping of DNA around nucleosomes blocks the access of other protein factors to this DNA, and this can silence gene expression and other chromosomal processes.
To enable access to the underlying DNA, nucleosomes must be mobilized, restructured, or ejected. As nucleosomes themselves are stable particles with limited mobility, their dynamic movement requires the action of nucleosome-modifying complexes and nucleosome-remodeling complexes (remodelers).
Remodelers display three main functions:
- The ISWI Remodeler organizes nucleosomes after their deposition following replication;
- The SWI/SNF remodeler family disorganizes, slides, and ejects nucleosomes; and
- The SWRI family changes nucleosome composition.
Modifying complexes add or removes covalent modifications (such as acetylation or methylation) at particular locations on the histone proteins. These modifications are recognized by remodeler complexes and other chromatin regulators. Remodeler complexes restructure, reposition, and eject nucleosomes that bear particular modification patterns, thus providing access to the DNA.
Thus, nucleosome-modifying and nucleosome-remodeling complexes work together to guide the ordered recruitment of transcriptional regulators to particular loci on chromosomes. Many important questions remain regarding the functions of histone variants, modification complexes, and remodelers.
To understand their roles better, we are combining:
- and genomic approaches.