Alexander M. Mazo, PhD

Epigenetics mainly addresses maintenance of gene expression patterns by the structure of chromatin and modifications of DNA. Chromatin-related epigenetic mechanisms of maintenance of gene expression in daughter cells are essential for normal development, and their alterations cause numerous diseases including cancer. Research in my lab focuses on understanding several key epigenetic issues: how gene expression patterns are maintained during DNA replication and mitosis, how they are changed during development and cell differentiation, and how they are altered in cancer and other diseases.

The nature of epigenetic bookmarking is currently unclear, since it is not known how the process of DNA replication in eukaryotes affects association of chromosomal and transcriptional proteins with DNA. It is also not known whether nascent RNAs are dissociated from DNA and when the new round of transcription is initiated after replication. We found previously that in differentiating cells, numerous chromatin-modifying proteins are associated with DNA during DNA replication. However, major modified histone isoforms, the generally accepted epigenetic bookmarks, are detected on nascent DNA only some time after replication, implying that the widely accepted model for epigenetic bookmarking has to be re-examined. Using a number of recently developed techniques that allow detecting association of RNA and proteins with nascent DNA, we are currently investigating the fate of the RNA-transcriptional complex in epigenetic bookmarking. These studies may help to develop new models for epigenetic marking during DNA replication.

While gene expression patterns and thus epigenetic maintenance change during development, the mechanisms that allow these changes to occur are not clear. We recently discovered that differentiation of stem/progenitor cells of multiple origins requires transient de-condensation of post-replicative, nascent chromatin at repressed genes. This facilitates binding of lineage-specific transcription factors with their binding sites on nascent DNA and leads to changes in transcriptional and epigenetic programs of induced cells. These mechanisms are common in all tested differentiating cells, human and mouse embryonic stem cells, blood progenitor cells, and even during differentiation of more specialized cells, like T-cells and myofibroblsts. These findings may have a number of disease-related implications. On one hand, the knowledge of these mechanisms may create essential tools of manipulating the structure of nascent chromatin that may prevent major differentiation-related diseases like fibrosis. On the other hand, this creates a number of possibilities to prevent proliferation and survival of different types of cancer cells. Thus, the knowledge of the basic epigenetic mechanisms may help in devising new strategies of preventing differentiation-related diseases and in creating new tools in cancer treatment.

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