Gene expression of subtypes of neocortical projection neurons over developmental time is correlated with cell class-specific chromatin accessibility
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE116146 | GEO | 2019/06/21
REPOSITORIES: GEO
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Project description:The mammalian neocortex comprises enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a unique sensitivity in the development of neurons expressing Satb2, a determinant of upper cortical layers, to translation rates. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates are inherent features of cortical neuron subtypes. In a small molecule screening, we reveal Ire1a as a regulator of Satb2 and global translation rates. In the developing brain, Ire1a coordinates ribosome traffic and the expression of eIF4A1. Furthermore, we demonstrate that the mRNA translation of Satb2 depends on its 5’-untranlsated region and requires eIF4A1 helicase activity. Here, we show that cortical neuron diversity is generated by mechanisms operating beyond the gene transcription, with Ire1a-safeguarded proteostasis serving as an essential regulator of brain development factors, and ribosomal proteins. Translation rates distinguish early and late neuronal progenitors and early- and late-born postmitotic neurons, indicative of developmental stage- and differentiation-specific requirements for protein synthesis rates in the formation of upper and deeper cortical layers. We demonstrate that specification and polarization of upper layer neurons is uniquely sensitive to translation rate, in contrast to deep layer neurons. Our data shed light onto the post-transcriptional source of cellular diversity in the developing cortex and unveils stress-independent homeostatic functions of Ire1a.
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Project description:The neocortex is comprised of six neuronal layers that are derived in an inside-out sequence. Neurog2, a proneural gene encoding a basic-helix-loop-helix transcription factor, is required and sufficient to specify the fate of only early-born, deep-layer neurons, despite being expressed throughout the cortical neurogenic period. To identify potential inhibitors of Neurog2 function, we used a TAP-tagging screen, identifying L3mbtl3, a histone methyl-lysine binding protein that interacts with Rnf2 in Polycomb Repressive Complex 1 (PRC1), as a novel Neurog2 interactor. We found that L3mbtl3 is co-expressed with Neurog2 and other PRC1 genes in cortical progenitors. In L3mbtl3 knock-out (KO) cortices, upper-layer neurons are generated in reduced numbers, and instead, the cortical progenitor pool is expanded. Transcriptomic analyses of L3mbtl3 KO cortices at early and mid neurogenesis revealed a striking upregulation of negative regulators of transcription, including Rest, a repressor of many neurogenic genes, and an associated downregulation of neuronal differentiation and maturation genes. Notably, transcriptomic changes occur in the absence of any changes to chromatin structure, suggesting that L3mbtl3 influences gene transcription directly and not via changes to the chromatin. Instead, L3mbtl3 represses Neurog2 transcriptional activity in vitro and blocks cortical progenitor cell maturation and neuronal migration in vivo by altering the expression of scaffold genes. L3mbtl3 is thus an essential negative regulator of cortical neurogenesis.
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Project description:The neocortex is comprised of six neuronal layers that are derived in an inside-out sequence. Neurog2, a proneural gene encoding a basic-helix-loop-helix transcription factor, is required and sufficient to specify the fate of only early-born, deep-layer neurons, despite being expressed throughout the cortical neurogenic period. To identify potential inhibitors of Neurog2 function, we used a TAP-tagging screen, identifying L3mbtl3, a histone methyl-lysine binding protein that interacts with Rnf2 in Polycomb Repressive Complex 1 (PRC1), as a novel Neurog2 interactor. We found that L3mbtl3 is co-expressed with Neurog2 and other PRC1 genes in cortical progenitors. In L3mbtl3 knock-out (KO) cortices, upper-layer neurons are generated in reduced numbers, and instead, the cortical progenitor pool is expanded. Transcriptomic analyses of L3mbtl3 KO cortices at early and mid neurogenesis revealed a striking upregulation of negative regulators of transcription, including Rest, a repressor of many neurogenic genes, and an associated downregulation of neuronal differentiation and maturation genes. Notably, transcriptomic changes occur in the absence of any changes to chromatin structure, suggesting that L3mbtl3 influences gene transcription directly and not via changes to the chromatin. Instead, L3mbtl3 represses Neurog2 transcriptional activity in vitro and blocks cortical progenitor cell maturation and neuronal migration in vivo by altering the expression of scaffold genes. L3mbtl3 is thus an essential negative regulator of cortical neurogenesis.
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Project description:Cortical development is under control of transcriptional programs that are orchestrated by activation of key determinants such as transcription factors. But stable inheritance of temporo-spatial activity of factors influencing cell fate and regionalization in different layers is only partly understood. We report that chromatin methylation at H3K79 transmits cell fate and layering information from early to late progenitors. Activity of DOT1L, mediating H3K79 methylation, prevents premature cell cycle exit by increasing expression of genes regulating asymmetric cell division (Vangl2, Cenpj). Transcriptional programs characteristic for upper layer neurons are less active in Dot1l-deficient mice already at developmental stages that precede upper layer neuron generation. DOT1L activates expression of many key determinants such as Cux1, Cux2, Satb2 or Pou3f3. Additionally, DOT1L affects transcription of Sox family members, suggesting an evolutionary conserved mechanism. In part, DOT1L and H3K79me2 replace inactivating H3K9me3 at Sox family promoters and allow for transcriptional activation during neural differentiation.
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Project description:Cortical development is under control of transcriptional programs that are orchestrated by activation of key determinants such as transcription factors. But stable inheritance of temporo-spatial activity of factors influencing cell fate and regionalization in different layers is only partly understood. We report that chromatin methylation at H3K79 transmits cell fate and layering information from early to late progenitors. Activity of DOT1L, mediating H3K79 methylation, prevents premature cell cycle exit by increasing expression of genes regulating asymmetric cell division (Vangl2, Cenpj). Transcriptional programs characteristic for upper layer neurons are less active in Dot1l-deficient mice already at developmental stages that precede upper layer neuron generation. DOT1L activates expression of many key determinants such as Cux1, Cux2, Satb2 or Pou3f3. Additionally, DOT1L affects transcription of Sox family members, suggesting an evolutionary conserved mechanism. In part, DOT1L and H3K79me2 replace inactivating H3K9me3 at Sox family promoters and allow for transcriptional activation during neural differentiation.
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Project description:Cortical development is under control of transcriptional programs that are orchestrated by activation of key determinants such as transcription factors. But stable inheritance of temporo-spatial activity of factors influencing cell fate and regionalization in different layers is only partly understood. We report that chromatin methylation at H3K79 transmits cell fate and layering information from early to late progenitors. Activity of DOT1L, mediating H3K79 methylation, prevents premature cell cycle exit by increasing expression of genes regulating asymmetric cell division (Vangl2, Cenpj). Transcriptional programs characteristic for upper layer neurons are less active in Dot1l-deficient mice already at developmental stages that precede upper layer neuron generation. DOT1L activates expression of many key determinants such as Cux1, Cux2, Satb2 or Pou3f3. Additionally, DOT1L affects transcription of Sox family members, suggesting an evolutionary conserved mechanism. In part, DOT1L and H3K79me2 replace inactivating H3K9me3 at Sox family promoters and allow for transcriptional activation during neural differentiation.
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