Odorant Sensory Input Modulates DNA Secondary Structure Formation and Heterogeneous Ribonucleoprotein Recruitment on the Tyrosine Hydroxylase and Glutamic Acid Decarboxylase 1 Promoters in the Olfactory Bulb

Abstract

Adaptation of neural circuits to changes in sensory input can modify several cellular processes within neurons, including neurotransmitter biosynthesis levels. For a subset of olfactory bulb interneurons, activity-dependent changes in GABA are reflected by corresponding changes in <i>Glutamate decarboxylase 1</i> (<i>Gad1</i>) expression levels. Mechanisms regulating <i>Gad1</i> promoter activity are poorly understood, but here we show that a conserved G:C-rich region in the mouse <i>Gad1</i> proximal promoter region both recruits heterogeneous nuclear ribonucleoproteins (hnRNPs) that facilitate transcription and forms single-stranded DNA secondary structures associated with transcriptional repression. This promoter architecture and function is shared with <i>Tyrosine hydroxylase</i> (<i>Th</i>), which is also modulated by odorant-dependent activity in the olfactory bulb. This study shows that the balance between DNA secondary structure formation and hnRNP binding on the mouse <i>Th</i> and <i>Gad1</i> promoters in the olfactory bulb is responsive to changes in odorant-dependent sensory input. These findings reveal that <i>Th</i> and <i>Gad1</i> share a novel transcription regulatory mechanism that facilitates sensory input-dependent regulation of dopamine and GABA expression.<b>SIGNIFICANCE STATEMENT</b> Adaptation of neural circuits to changes in sensory input can modify several cellular processes within neurons, including neurotransmitter biosynthesis levels. This study shows that transcription of genes encoding rate-limiting enzymes for GABA and dopamine biosynthesis (<i>Gad1</i> and <i>Th</i>, respectively) in the mammalian olfactory bulb is regulated by G:C-rich regions that both recruit heterogeneous nuclear ribonucleoproteins (hnRNPs) to facilitate transcription and form single-stranded DNA secondary structures associated with repression. hnRNP binding and formation of DNA secondary structure on the <i>Th</i> and <i>Gad1</i> promoters are mutually exclusive, and odorant sensory input levels regulate the balance between these regulatory features. These findings reveal that <i>Th</i> and <i>Gad1</i> share a transcription regulatory mechanism that facilitates odorant-dependent regulation of dopamine and GABA expression levels.