Synaptic transmission leads to the activation of a transcriptional program in the postsynaptic cell that is critical for long-lasting changes in synapse development and plasticity. A number of neurodevelopmental disorders have been linked to abnormalities in this activity-regulated transcriptional network, indicating that these signaling pathways are critical for cognitive development and function. For many years attention has been focused on identifying the proximal promoter regions of activity-regulated genes and on assessing activity- dependent gene function. During the previous funding period, we used genome-wide sequencing methods to discover thousands of neuronal activity-regulated distal enhancer elements that function in primary mouse cortical cultures, indicating that by focusing on proximal promoter elements we had failed to identify the vast majority of neuronal activity-responsive cis-regulatory elements. The discovery of activity-regulated enhancer is of significant interest because there is accumulating evidence implicating distal cis-regulatory elements in human disease. However, the basic mechanisms of stimulus-responsive enhancer function in neurons are not yet understood and we lack methods to rapidly and reversibly disrupt enhancer and promoter function so that the roles of these regulatory elements, and the genes they control, can be assessed. In the absence of such methods, it has been difficult to characterize the specific contributions of these gene regulatory mechanisms to neural development and plasticity. To begin to address these issues, we propose (1) to develop a generalizable approach to disrupt neuronal cis-regulatory element function, and (2) to use this new technology to test the importance of regulatory elements within the gene encoding Brain-derived neurotrophic factor (BDNF) for inhibitory circuit plasticity. Taken together, the proposed experiments will provide insight into regions of the genome that are not yet characterized but likely to have crucial functions during nervous system development and function. These studies will also lead to the development of new methods for the study of cis-regulatory elements, provide a better understanding of the mechanisms by which neural activity shapes the developing and mature nervous system, and yield new insights into the importance of activity-responsive cis- regulatory elements for human cognition and disease.
Neuronal activity triggers the expression of new genes, which play a critical role in aspects of neural development and human cognitive function. The proposed study will seek to develop new methods to explore the regulation and function of this gene expression program in the central nervous system.
|Mardinly, A R; Spiegel, I; Patrizi, A et al. (2016) Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 531:371-5|
|Andzelm, Milena M; Cherry, Timothy J; Harmin, David A et al. (2015) MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers. Neuron 86:247-63|
|Malik, Athar N; Vierbuchen, Thomas; Hemberg, Martin et al. (2014) Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat Neurosci 17:1330-9|
|Spiegel, Ivo; Mardinly, Alan R; Gabel, Harrison W et al. (2014) Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell 157:1216-29|
|Bloodgood, Brenda L; Sharma, Nikhil; Browne, Heidi Adlman et al. (2013) The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature 503:121-5|
|Chahrour, Maria H; Yu, Timothy W; Lim, Elaine T et al. (2012) Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet 8:e1002635|
|Hemberg, Martin; Gray, Jesse M; Cloonan, Nicole et al. (2012) Integrated genome analysis suggests that most conserved non-coding sequences are regulatory factor binding sites. Nucleic Acids Res 40:7858-69|
|Ross, Sarah E; McCord, Alejandra E; Jung, Cynthia et al. (2012) Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly. Neuron 73:292-303|
|West, Anne E; Greenberg, Michael E (2011) Neuronal activity-regulated gene transcription in synapse development and cognitive function. Cold Spring Harb Perspect Biol 3:|
|Kim, Tae-Kyung; Hemberg, Martin; Gray, Jesse M et al. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182-7|
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