Synthetic Epigenetics | NYU Langone Health

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Boeke Lab Research Synthetic Epigenetics

Synthetic Epigenetics

Although variations in protein coding and non-coding DNA contribute to the biology of the organism, there is another layer that drives heritable traits: chromatin structure. DNA within living cells exists in an organized protein packaging system, chromatin, which controls when genes are produced or silenced. This "epigenome" equips many eukaryotes with the ability to generate stable and distinct cell types from a single identical genome. This flexibility originates from interconnected chromatin organizing pathways acting at multiple length scales across chromosomes to regulate gene expression, maintain cell identity and adapt to environmental changes. How do cells procure their particular chromatin structure?

We aim to decipher the complexity of human chromatin organization by rewriting the system in budding yeast using a progressive bottom-up approach. Consequently, we can dissect the complicated regulatory circuits that control the production of functional proteins from DNA in humans, other animals, and other multicellular organisms. Our bottom-up strategy of rewriting human chromatin features occurs at four levels: histones, heterochromatin, euchromatin and Topologically Associating Domain (TAD) structures.

(Objective 1) Histones: expanding the ability to generate diverse human histone variant architectures. (Objective 2) Heterochromatin: human pathways such as Polycomb Group Proteins will be imported into budding yeast to generate the repressive histone Post-Translational Modifications (PTMs) H3K27me, H3K9me, H2AK119ub and CpG methylation.  (Objective 3) Euchromatin: the COMPASS complex in yeast will be replaced by the human pathway that generates the activating histone PTM H3K4me.  (Objective 4) Topologically Associating Domain (TAD) structures: human-like TAD structures will be engineered using human cohesin and CTCF complexes.

Much is still unknown about how chromatin regulates the production of proteins, but a better understanding could lead to advances in our knowledge of how organisms adapt to new environments or how better to treat certain diseases.