Regulatory Strategies for the Control of Activity-Dependent Gene Expression in a Single Neuron Type

Project Summary
A neuron’s activity history is precisely encoded in its gene expression profile. This molecular encoding is
achieved via transcriptional regulatory programs specific to distinct features of activity patterns. In particular, an
activating stimulus evokes unique, temporally segregated waves of transcription as a function of its duration.
The regulatory mechanisms which orchestrate the transduction of stimuli duration into temporal waves of
transcription have been described in heterogenous populations of neuronal cell types. However, whether
similar or distinct mechanisms operate to translate activity patterns into specific expression programs in
defined neuronal subtypes in vivo is unknown. We have established AFD, a pair of sensory neurons in C.
elegans, as a cellular model in which to describe the regulatory pathways that transduce neuronal activity into
gene expression changes. Via AFD specific RNA-Seq, we have shown that the duration of temperature
experience is encoded in AFD by temporal waves of gene expression reflecting similar waves described in
more complex organisms. These temporally regulated gene expression changes are critical for modulating
AFD functions. Preliminarily, bioinformatics analyses and experimental manipulations suggest that the CREB
transcription factor together with the SPR-4/REST repressor shape the temporal kinetics of temperature-
induced upregulation in a subset of genes. The goal of this proposal is to provide a systematic mechanistic
description of the molecular pathways by which the duration of temperature experience is encoded in the
molecular profile of AFD. Experiments proposed in Aim 1 will employ a multifaceted approach including
bioinformatics analyses, experimental deletions, and AFD-specific ATAC-Seq to identify cis-acting regulatory
motifs which direct activity-dependent transcription in AFD as a function of stimulus duration, and to determine
their role in the epigenetic control of gene expression. In Aim 2, these motifs will be linked to their cognate
transcription factors (TFs), and the mechanisms by which antagonism between activator and repressor TFs
shape gene expression programs will be investigated. Together, results from this work will provide a
comprehensive description of how a defined environmental experience is precisely translated into gene
expression programs in an individual neuron type in vivo to modulate neuronal properties.

Grant Number: 5F31NS137615-03
NIH Institute/Center: NIH
Principal Investigator: Samuel Bates