Inactivation of DET1 causes neurological defects and lethality in mice and humans I
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ABSTRACT:
PROVIDER: PRJNA1133052 | ENA |
REPOSITORIES: ENA
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Project description:COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Its transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here we show that a homozygous DET1R26W mutation that is linked to lethal developmental abnormalities in humans disrupts DET1 binding to DDB1 and compromises E3 ligase function. Human-induced pluripotent stem cells bearing the homozygous DET1R26W mutation expressed ETV4 and ETV5 highly, had alterations in mitochondrial protein expression, and exhibited impaired neuronal differentiation. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.
2025-01-28 | GSE271767 | GEO
Project description:COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Its transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here we show that a homozygous DET1R26W mutation that is linked to lethal developmental abnormalities in humans disrupts DET1 binding to DDB1 and compromises E3 ligase function. Human-induced pluripotent stem cells bearing the homozygous DET1R26W mutation expressed ETV4 and ETV5 highly, had alterations in mitochondrial protein expression, and exhibited impaired neuronal differentiation. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.
2025-01-28 | GSE271764 | GEO
Project description:Inactivation of DET1 causes neurological defects and lethality in mice and humans II
| PRJNA1133057 | ENA
Project description:COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Its transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here we show that a homozygous DET1R26W mutation that is linked to lethal developmental abnormalities in humans disrupts DET1 binding to DDB1 and compromises E3 ligase function. Human-induced pluripotent stem cells bearing the homozygous DET1R26W mutation expressed ETV4 and ETV5 highly, had alterations in mitochondrial protein expression, and exhibited impaired neuronal differentiation. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.
2024-06-26 | MSV000095151 | MassIVE
Project description:rs09-01_det1 - photomorphogenesis - - Identification of the genes deregulated in det1-1 when seedlings grow in light or in dark (dark increase morphological differences between det1-1 and wild-type) - Expression profile of seedlings grown in dark then exposed to light - etiolated seedlings (5days) are briefly exposed to light to induce developmental transition between skoto- and photomorphogenesis without visible change in plant morphology and differences between col0 and the mutant det1-1 grown in light or in dark Keywords: treatment variations 6 dye-swap - CATMA arrays
2010-04-30 | E-GEOD-19843 | biostudies-arrayexpress
Project description:rs09-01_det1 - photomorphogenesis - - Identification of the genes deregulated in det1-1 when seedlings grow in light or in dark (dark increase morphological differences between det1-1 and wild-type) - Expression profile of seedlings grown in dark then exposed to light - etiolated seedlings (5days) are briefly exposed to light to induce developmental transition between skoto- and photomorphogenesis without visible change in plant morphology and differences between col0 and the mutant det1-1 grown in light or in dark Keywords: treatment variations
2010-05-01 | GSE19843 | GEO
Project description:DE-ETIOLATED1 (DET1) is a negative regulator of plant photomorphogenesis acting as a component of the C3D complex, which can further associate to CULLIN4 to form a CRL4C3D E3 ubiquitin ligase. CRL4C3D is thought to act together with CRL4COP1SPA ubiquitin ligase, to promote the ubiquitin-mediated degradation of the master regulatory transcription factor ELONGATED HYPOCOTYL5 (HY5), thereby controlling photomorphogenic gene regulatory networks. Yet, functional links between COP1 and DET1 have long remained elusive. Here, upon mass spectrometry identification of DET1 and COP1-associated proteins, we provide in vivo evidence that DET1 associates with COP1 to promote its destabilization, a process necessary to dampen HY5 protein abundance. By regulating HY5 over-accumulation, DET1 is critical to avoid its association to second-site loci, including many PIF3 target genes. Accordingly, excessive HY5 levels result in an increased HY5 repressive activity and are sufficient to trigger fusca-like phenotypes otherwise observed typically in COP1 and COP9 signalosome mutant seedlings. This study therefore identifies that DET1-mediated regulation of COP1 stability tunes down HY5 cistrome and avoids hyper-photomorphogenic responses that might compromise plant viability.
2021-09-09 | GSE155147 | GEO
Project description:DE-ETIOLATED 1 (DET1) is an evolutionarily conserved component of the ubiquitination machinery that mediates the destabilization of key regulators of cell differentiation and proliferation in multicellular organisms. In this study, we provide evidence from Arabidopsis that DET1 is essential for the regulation of histone H2B monoubiquitination (H2Bub) over most genes by controlling the stability of a plant deubiquitination module (DUBm). In contrast with yeast and metazoan DUB modules that are associated with the large SAGA complex, the Arabidopsis DUBm only comprises three proteins (hereafter named SGF11, ENY2 and UBP22) and appears to act independently as a major H2Bub deubiquitinase activity. Our study further unveils that DET1-DDB1-Associated-1 (DDA1) protein interacts with SGF11 in vivo, linking the DET1 complex to light-dependent ubiquitin-mediated proteolytic degradation of the DUBm. Collectively, these findings uncover a signaling path controlling DUBm availability, potentially adjusting H2Bub turnover capacity to the cell transcriptional status.
2018-08-31 | GSE112952 | GEO
Project description:DE-ETIOLATED 1 (DET1) is an evolutionarily conserved component of the ubiquitination machinery that mediates the destabilization of key regulators of cell differentiation and proliferation in multicellular organisms. In this study, we provide evidence from Arabidopsis that DET1 is essential for the regulation of histone H2B monoubiquitination (H2Bub) over most genes by controlling the stability of a plant deubiquitination module (DUBm). In contrast with yeast and metazoan DUB modules that are associated with the large SAGA complex, the Arabidopsis DUBm only comprises three proteins (hereafter named SGF11, ENY2 and UBP22) and appears to act independently as a major H2Bub deubiquitinase activity. Our study further unveils that DET1-DDB1-Associated-1 (DDA1) protein interacts with SGF11 in vivo, linking the DET1 complex to light-dependent ubiquitin-mediated proteolytic degradation of the DUBm. Collectively, these findings uncover a signaling path controlling DUBm availability, potentially adjusting H2Bub turnover capacity to the cell transcriptional status.
2018-08-31 | GSE112951 | GEO
Project description:DE-ETIOLATED 1 (DET1) is an evolutionarily conserved component of the ubiquitination machinery that mediates the destabilization of key regulators of cell differentiation and proliferation in multicellular organisms. In this study, we provide evidence from Arabidopsis that DET1 is essential for the regulation of histone H2B monoubiquitination (H2Bub) over most genes by controlling the stability of a plant deubiquitination module (DUBm). In contrast with yeast and metazoan DUB modules that are associated with the large SAGA complex, the Arabidopsis DUBm only comprises three proteins (hereafter named SGF11, ENY2 and UBP22) and appears to act independently as a major H2Bub deubiquitinase activity. Our study further unveils that DET1-DDB1-Associated-1 (DDA1) protein interacts with SGF11 in vivo, linking the DET1 complex to light-dependent ubiquitin-mediated proteolytic degradation of the DUBm. Collectively, these findings uncover a signaling path controlling DUBm availability, potentially adjusting H2Bub turnover capacity to the cell transcriptional status.
2018-08-31 | GSE112950 | GEO