Life Sciences Division
Lawrence Berkeley National Laboratory
Embryonic stem (ES) cells have enormous capacity to self-renew while maintaining the ability to differentiate into all adult cell types. It has been shown that ES cell differentiation is accompanied by changes in chromatin accessibility at several key developmental genes, including a large-scale opening of the HoxB locus. We hypothesize that global reorganization of chromatin structure must take place in order for ES cells to differentiate into specific cell lineages. There may be proteins which direct such chromatin reorganization in ES cells during differentiation.
We have been studying a protein, SATB1, which functions as a chromatin organizer in thymocytes and activated T cells. SATB1 has a nuclear distribution resembling a cage-like structure, surrounding heterochromatin. SATB1 folds chromatin by tethering specialized genomic DNA segments, which bear an unusual physical property (base-unpairing region; BURs), to the SATB1 cage-like structure. SATB1 targets chromatin remodeling/modifying enzymes, such as HDAC1 and ISWI to BURs, and thereby regulates regional histone modification status and nucleosome positioning. Having such a function, SATB1 ablation leads to disruption of hundreds of genes, resulting in an arrest in T cell development. Our laboratory is examining the function of SATB1, its homolog SATB2, and other proteins with DNA binding specificity similar to the SATB family proteins, to see if any of them has the ability to reorganize chromatin as ES cells commit to specific cell lineages. We are interested in determining which sets of genes are targeted, how chromatin is functionally organized via looping, and how chromatin structure is marked by epigenetic modification during ES cell differentiation into the neuronal and T cell lineages.