Optical control of mammalian endogenous transcription and epigenetic states.

Nature
Authors
Keywords
Abstract

The dynamic nature of gene expression enables cellular programming, homeostasis and environmental adaptation in living systems. Dissection of causal gene functions in cellular and organismal processes therefore necessitates approaches that enable spatially and temporally precise modulation of gene expression. Recently, a variety of microbial and plant-derived light-sensitive proteins have been engineered as optogenetic actuators, enabling high-precision spatiotemporal control of many cellular functions. However, versatile and robust technologies that enable optical modulation of transcription in the mammalian endogenous genome remain elusive. Here we describe the development of light-inducible transcriptional effectors (LITEs), an optogenetic two-hybrid system integrating the customizable TALE DNA-binding domain with the light-sensitive cryptochrome 2 protein and its interacting partner CIB1 from Arabidopsis thaliana. LITEs do not require additional exogenous chemical cofactors, are easily customized to target many endogenous genomic loci, and can be activated within minutes with reversibility. LITEs can be packaged into viral vectors and genetically targeted to probe specific cell populations. We have applied this system in primary mouse neurons, as well as in the brain of freely behaving mice in vivo to mediate reversible modulation of mammalian endogenous gene expression as well as targeted epigenetic chromatin modifications. The LITE system establishes a novel mode of optogenetic control of endogenous cellular processes and enables direct testing of the causal roles of genetic and epigenetic regulation in normal biological processes and disease states.

Year of Publication
2013
Journal
Nature
Volume
500
Issue
7463
Pages
472-6
Date Published
2013 Aug 22
ISSN
1476-4687
URL
DOI
10.1038/nature12466
PubMed ID
23877069
PubMed Central ID
PMC3856241
Links
Grant list
P50 HG005550 / HG / NHGRI NIH HHS / United States
DP1-MH100706 / DP / NCCDPHP CDC HHS / United States
DP1 MH100706 / MH / NIMH NIH HHS / United States
R01 NS073124 / NS / NINDS NIH HHS / United States
R01-NS073124 / NS / NINDS NIH HHS / United States
R01 DK097768 / DK / NIDDK NIH HHS / United States
P50-HG005550 / HG / NHGRI NIH HHS / United States