STRUCTURE-FUNCTIONAL RELATIONSHIP IN CHROMATINIn eukaryotic cells, DNA is coiled around repeated histone octamers to form chains of nucleosomes that are further folded into higher order chromatin structure. A special set of histone modifications interacts with architectural chromosomal proteins to direct higher order folding into either the relatively dispersed transcriptionally active euchromatin or condensed and repressed heterochromatin. Our current research is focused on the following aspects of chromatin higher order folding and its remodeling associated with cell differentiation:
CHROMATIN FOLDING AND BRIDGING.
Chromatin condensation is mediated by two separable structural transitions: folding of a single nucleosome array and bridging caused by protein factors gluing two or more separate arrays together. We have cloned and studied the first nonhistone chromatin bridging factor, MENT. In terminally differentiated cells, MENT binds chromatin marked by histone H3 methylation at lysine 9 to promote its bridging and condensation (see the scheme below). Our work suggested that chromatin bridging factors promote heterochromatin formation through lateral interdigitation of nucleosome zigzag chains. We currently study MENT protein 3D structure and the geometry of nucleosome arrays aiming to find the structural principles that direct the nucleosome array compaction into either the folding mode (compatible with transcription) or the bridging mode that turns nucleosome arrays into stably condensed heterochromatin.
EPIGENETIC HETEROCHROMATIN MARKERS IN CELL DIFFERENTIATION AND CANCER.
Terminally differentiated cells accumulate a large amount of repressed heterochromatin. In proliferating cells, heterochromatin is controlled by epigenetic chromatin factors, most importantly histone H3 methylation at lysine 9 and heterochromatin protein HP1. We found that in terminally differentiated cells, HP1 is dramatically reduced (and apparently replaced by chromatin-bridging factors, see the scheme below) while the histone H3 methylation is relocated and forms compact clusters at the periphery of constitutive heterochromatin. We are now studying the chromatin structure and epigenetic changes associated with incomplete differentiation in human breast cancer and myeloid leukemia cells. The aim of this research is to provide a way to ensure chromatin condensation for "differential therapy" of cancer and other human disorders associated with incomplete cell differentiation. | 
