ATP-dependent chromatin remodelers are pivotal in gene regulation, cell development, and cancer. These complexes can move and space nucleosomes, exchange particular histone variants in order to change the composition of chromatin, and disassemble/assemble nucleosomes. The Bartholomew lab studies the SWI/SNF family of remodelers as well as the ISWI and INO80 families.
SWI/SNF Chromatin Remodelers
One subfamily of remodelers called the SWI/SNF family is well conserved from yeast to human and is frequently mutated in association with cancer. There are estimated to be up to 100 different forms of the SWI/SNF complex in humans and many of these are tissue and cell type specific. SWI/SNF can either activate or repress transcription, is frequently recruited to the promoter and enhancer regions of genes, and may also travel with RNA polymerase II as it traverses the gene body.
From next-generation sequencing (NGS) of exomes, the genes encoding for the subunits of SWI/SNF have been found to be the targets frequently mutated that lead to cancer. Research in the Bartholomew lab is focused on understanding the molecular modes of action for SWI/SNF, the functional roles of its subunits and associated domains, and the impact of changes in the complex on cellular differentiation.
ISWI and INO80 Chromatin Remodelers
The Bartholomew lab is also interested in other ATP-dependent chromatin remodelers such as the ISWI and INO80 families. These complexes have, besides the ability to move nucleosomes and change the spacing between nucleosomes, the capacity to assemble nucleosomes de novo and to exchange out variants of the H2A-H2B dimer.
The over-expression of a subunit of one of these complexes called Rsf1 has been observed to promote several types of cancer. The RSF complex can assemble histone octamers into nucleosomes without any histone chaperones, and RSF is important for the formation of a highly specialized chromatin structure at centromeres. These families of complexes have a dependence on linker DNA and remodel chromatin in a manner distinct from that of the SWI/SNF complexes.