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.