Recreating molecular memories: imaging the mechanics of chromosome assembly and the birth of cell identity

The gene expression patterns that define specific cell types are determined in part by epigenetic information encoded in histone marks that guide chromatin organization.

During chromosome duplication, new histones lacking this information must be deposited to support the doubling of chromatin.

However, the molecular mechanism of histone deposition and the coordination pathways that ensure epigenetic information is transmitted remain unknown.

Determining the mechanics of chromosome assembly promises to open a new frontier in our understanding of the propagation of cell fate decisions that support multicellular life.

Due to the antiparallel configuration of DNA, different DNA synthesis mechanisms are used on the daughter strands during DNA replication. How this is coordinated with the symmetric duplication of chromatin organization on daughter chromosomes is not known.

I hypothesize that the replisome contains an extensive network of molecular wiring encoding the fundamental logic that governs histone transfer and deposition that is essential for the preservation of epigenetic cell identity and chromosome integrity.

To discover this network, I propose a research program combining structural, biochemical, and single-molecule imaging approaches.

To gain access to critical missing information, we will develop techniques that reveal the dynamics of histone transfer and deposition independently on each daughter strand in real-time for single replisomes.The proposed research will determine the structural basis of new histone deposition, reveal the dynamics of replication-coupled chromatin assembly, and address how epigenetic states are re-established on daughter chromosomes.

Realizing these objectives will represent a major breakthrough in our understanding of the molecular mechanics of chromosome assembly, the transmission of epigenetic cell memory, and allow for transformative biomedical technologies through engineered reprogramming of epigenetic memories.