Robust regulatory architecture of pan-neuronal gene expression
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ABSTRACT:
PROVIDER: PRJNA779059 | ENA |
REPOSITORIES: ENA
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Project description:Panneuronally expressed genes, such as genes involved in the synaptic vesicle release cycle or in neuropeptide maturation, are critical for proper function of all neurons, but the transcriptional control mechanisms that direct such genes to all neurons of a nervous system remain poorly understood in any organism. We show here that six members of the CUT superfamily of homeobox genes, which are each panneuronally expressed, control panneuronal identity specification in C. elegans. Single mutants show barely any effects on panneuronal gene expression or global nervous system function, but such effects become apparent and progressively worsen upon removal of additional CUT family members. Phenotypes of compound mutants can be rescued non-discriminately by overexpression of individual family members, indicating that gene dosage is critical for CUT gene function. Genome-wide binding profiles as well as mutation of CUT binding sites by CRISPR/Cas9 genome engineering show that CUT genes directly control the expression of panneuronal features. Lastly, we found that CUT genes act in conjunction with neuron-type specific transcription factors to control panneuronal gene expression. In conclusion, our study provides a previously missing key insight into how neuronal gene expression programs are specified and reveals a highly buffered and robust mechanism that controls the most critical functional features of all neurons.
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Project description:Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation. In contrast, programs that are active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. Our work uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
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Project description:Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation. In contrast, programs that are active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. Our work uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
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Project description:Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation. In contrast, programs that are active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. Our work uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
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Project description:Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation. In contrast, programs that are active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. Our work uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
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Project description:Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. The regulatory strategies that neurons use during progressive development and maturation remain unclear. We present an integrated single-cell epigenomic and transcriptional analysis of individual classes of neurons from both mouse and marmoset neocortex, sampled during both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We find that in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use molecular regulatory programs with broader tissue distribution and greater evolutionary conservation. In contrast, programs that are active during later neuronal maturation implement more brain- and neuron-specific mechanisms showing greater evolutionary divergence. Our work uncovers a temporally-regulated shift in regulatory choices, likely reflecting unique evolutionary constraints on distinct events of neuronal development in the neocortex.
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