Engineering Epigenetic Regulation Using Synthetic Read-Write Modules

Minhee Park; Nikit Patel; Albert J Keung; Ahmad S Khalil

doi:10.1016/j.cell.2018.11.002

Engineering Epigenetic Regulation Using Synthetic Read-Write Modules

Cell. 2019 Jan 10;176(1-2):227-238.e20. doi: 10.1016/j.cell.2018.11.002. Epub 2018 Dec 6.

Authors

Minhee Park¹, Nikit Patel¹, Albert J Keung², Ahmad S Khalil³

Affiliations

¹ Biological Design Center, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
² Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27606, USA. Electronic address: ajkeung@ncsu.edu.
³ Biological Design Center, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address: khalil@bu.edu.

Abstract

Chemical modifications to DNA and histone proteins are involved in epigenetic programs underlying cellular differentiation and development. Regulatory networks involving molecular writers and readers of chromatin marks are thought to control these programs. Guided by this common principle, we established an orthogonal epigenetic regulatory system in mammalian cells using N6-methyladenine (m6A), a DNA modification not commonly found in metazoan epigenomes. Our system utilizes synthetic factors that write and read m6A and consequently recruit transcriptional regulators to control reporter loci. Inspired by models of chromatin spreading and epigenetic inheritance, we used our system and mathematical models to construct regulatory circuits that induce m6A-dependent transcriptional states, promote their spatial propagation, and maintain epigenetic memory of the states. These minimal circuits were able to program epigenetic functions de novo, conceptually validating "read-write" architectures. This work provides a toolkit for investigating models of epigenetic regulation and encoding additional layers of epigenetic information in cells.

Keywords: DNA methylation; N6-methyladenine; cell engineering; chromatin; epigenetic memory; epigenetics; gene regulation; read-write; synthetic biology.

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