RPB1 ChIP-Seq of adrenal glands tissue from Wild Type (WT) and Armc5 knockout mice
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ABSTRACT:
PROVIDER: PRJNA717038 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14064467_1.fastq.gz | Fastqsanger.gz | |||
| SRR14064467_2.fastq.gz | Fastqsanger.gz | |||
| SRR14064468_1.fastq.gz | Fastqsanger.gz | |||
| SRR14064468_2.fastq.gz | Fastqsanger.gz | |||
| SRR14064469_1.fastq.gz | Fastqsanger.gz |
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Project description:RPB1-specific ubiquitin ligase (E3) controls the degradation of this largest subunit of Pol II and consequently the Pol II pool size. Although several RPB1-specific E3s have been documented, their function is only revealed in cells with massive DNA damage. We demonstrated that ARMC5 physically interacted with cullin3 (CUL3) and RPB1. ARMC5 is an armadillo domain-containing protein with unknown mechanisms of action. ARMC5 deletion caused significant RPB1 accumulation in all the major organs under a physiological condition in the absence of artificially induced DNA damage. This is accompanied by reduced RPB1 ubiquitination. In vitro ubiquitination assay proved that ARMC5, CUL3, and RBX1 formed an effective E3 for RPB1. RPB1 was confirmed as being highly accumulated in the adrenal gland nodules from PBMAH patients with mutations in the ARMC5 coding sequence. Surprisingly, the compromised RPB1 degradation did not lead to increased Pol II stalling according to ChIP-Seq, or a general decrease of gene transcription according to RNA-seq. On the contrary, among 1486 differentially expressed genes in the KO adrenal glands, 93.5% of them were upregulated, probably due to the enlarged Pol II pool size. Our results showed that the ARMC3-CUL3 E3 was the dominant E3 in normal cells and organs and controlled Pol II pool size. The abnormally large Pol II pool size due to ARMC5 mutation dysregulated a large number of genes that in turn led to many phenotypes, including PBMAH in humans.
2022-05-20 | GSE169578 | GEO
Project description:RPB1-specific ubiquitin ligase (E3) controls the degradation of this largest subunit of Pol II and consequently the Pol II pool size. Although several RPB1-specific E3s have been documented, their function is only revealed in cells with massive DNA damage. We demonstrated that ARMC5 physically interacted with cullin3 (CUL3) and RPB1. ARMC5 is an armadillo domain-containing protein with unknown mechanisms of action. ARMC5 deletion caused significant RPB1 accumulation in all the major organs under a physiological condition in the absence of artificially induced DNA damage. This is accompanied by reduced RPB1 ubiquitination. In vitro ubiquitination assay proved that ARMC5, CUL3, and RBX1 formed an effective E3 for RPB1. RPB1 was confirmed as being highly accumulated in the adrenal gland nodules from PBMAH patients with mutations in the ARMC5 coding sequence. Surprisingly, the compromised RPB1 degradation did not lead to increased Pol II stalling according to ChIP-Seq, or a general decrease of gene transcription according to RNA-seq. On the contrary, among 1486 differentially expressed genes in the KO adrenal glands, 93.5% of them were upregulated, probably due to the enlarged Pol II pool size. Our results showed that the ARMC3-CUL3 E3 was the dominant E3 in normal cells and organs and controlled Pol II pool size. The abnormally large Pol II pool size due to ARMC5 mutation dysregulated a large number of genes that in turn led to many phenotypes, including PBMAH in humans.
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Project description:ARMC5 is a protein containing an armadillo domain (ARM) and a BTB domain. Its gene knockout caused many phenotypes, including dwarfism, compromise T-cell immunity, and adrenal gland hypertrophy. ARMC5 mutation in humans is associated with bilateral macronodular adrenal gland hypertrophy. We found that AMC5 KO mice suffered from an increased incidence of neural tube defects (NTDs). We revealed that ARMC5 complexed with CUL3 and POLR2A and was part of a novel POLR2A-specific ubiquitin ligase (E3). This E3 was the dominant DNA damage-independent POLR2A-specific E3 in developing neural tubes and neural precursor cells under a physiological condition. ARMC5 gene knockout (KO) caused diminished POLR2A ubiquitination and compromised POLR2A degradation via proteasomes. Surprisingly, the absence of this E3 did not lead to generalized Pol II stalling and the subsequent generalized decrease of mRNA transcription but caused an enlarged Pol II pool size, which dysregulated 108 genes in NPCs, including some known to neural development. ARMC5 KO in the intestine downregulated FOHL1 expression, which was essential in folate absorption. Whole-exome sequencing of 511 myelomeningocele (MM) patients revealed nine highly deleterious mutations in the ARMC5 coding sequence. A significant deleterious mutation Arg429Cys found in MM patients drastically weakened the interaction between ARMC5 and POLR2A, supporting our hypothesis that such mutations in ARMC5 increased the NTD risks by compromising the POLR2A-specific E3 activity. Our results indicated that this novel ARMC5-CUL3-RBX1 E3 played a critical role in Pol II pool homeostasis, and ARMC5 mutation was a modifier of NTD risks in mice and humans.
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Project description:RNA-Seq of adrenal glands tissue from Wild Type (WT) and Armc5 knockout mice
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Project description:ARMC5 is a protein containing an armadillo domain (ARM) and a BTB domain. Its gene knockout caused many phenotypes, including dwarfism, compromise T-cell immunity, and adrenal gland hypertrophy. ARMC5 mutation in humans is associated with bilateral macronodular adrenal gland hypertrophy. We found that AMC5 KO mice suffered from an increased incidence of neural tube defects (NTDs). We revealed that ARMC5 complexed with CUL3 and POLR2A and was part of a novel POLR2A-specific ubiquitin ligase (E3). This E3 was the dominant DNA damage-independent POLR2A-specific E3 in developing neural tubes and neural precursor cells under a physiological condition. ARMC5 gene knockout (KO) caused diminished POLR2A ubiquitination and compromised POLR2A degradation via proteasomes. Surprisingly, the absence of this E3 did not lead to generalized Pol II stalling and the subsequent generalized decrease of mRNA transcription but caused an enlarged Pol II pool size, which dysregulated 108 genes in NPCs, including some known to neural development. ARMC5 KO in the intestine downregulated FOHL1 expression, which was essential in folate absorption. Whole-exome sequencing of 511 myelomeningocele (MM) patients revealed nine highly deleterious mutations in the ARMC5 coding sequence. A significant deleterious mutation Arg429Cys found in MM patients drastically weakened the interaction between ARMC5 and POLR2A, supporting our hypothesis that such mutations in ARMC5 increased the NTD risks by compromising the POLR2A-specific E3 activity. Our results indicated that this novel ARMC5-CUL3-RBX1 E3 played a critical role in Pol II pool homeostasis, and ARMC5 mutation was a modifier of NTD risks in mice and humans.
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Project description:RPB1 ChIP-Seq of NSC from Wild Type (WT) and Armc5 knockout mice
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Project description:The human adrenal glands are highly dynamic endocrine organs that are involved in the secretion of various hormones such as steroids and catecholamines. Here we present a single-nuclei and spatial transcriptomic analysis of healthy adult human adrenal glands to provide a complete adrenal gland atlas. With this, we show how such an atlas can be taken advantage when studying adrenocortical diseases, such as adrenocortical adenomas (ACA). Using nornal adrenal as reference, we showed a high intra-tumoural heterogeneity in the single-nuclei transcriptome of ACA, revealing the presence of specific cell populations associated with cortisol secretion and genetic background.
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Project description:Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex with thickened capsule. Cytomegalic changes were evident in the adrenal glands of fetal and adult cKO mice, and chromaffin cells were ectopically located at the periphery of the glands. The secretion of corticosterone in response to exogenous ACTH was blunted in cKO mice. Cells expressing gonadal-like markers, including Gata4, Amhr2, and Tcf21, accumulated in the adrenal capsule and subcapsule of cKO mice, suggesting aberrant adrenocortical progenitor/stem cell differentiation. Gonadectomy triggered the overexpression of sex steroidogenic differentiation markers, such as Lhcgr and Cyp17, in the adrenal glands of male and female cKO mice. Nulliparous female and orchiectomized male cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of nulliparous female Gata6 cKO mice. Our findings offer genetic proof of the longstanding hypothesis that GATA6 regulates the differentiation of steroidogenic progenitors into corticoid-producing cells. 3 replicates from both conditional knockout of Gata6 in the adrenal gland and control adrenal glands from non-knockout mice were compared
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Project description:Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex with thickened capsule. Cytomegalic changes were evident in the adrenal glands of fetal and adult cKO mice, and chromaffin cells were ectopically located at the periphery of the glands. The secretion of corticosterone in response to exogenous ACTH was blunted in cKO mice. Cells expressing gonadal-like markers, including Gata4, Amhr2, and Tcf21, accumulated in the adrenal capsule and subcapsule of cKO mice, suggesting aberrant adrenocortical progenitor/stem cell differentiation. Gonadectomy triggered the overexpression of sex steroidogenic differentiation markers, such as Lhcgr and Cyp17, in the adrenal glands of male and female cKO mice. Nulliparous female and orchiectomized male cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of nulliparous female Gata6 cKO mice. Our findings offer genetic proof of the longstanding hypothesis that GATA6 regulates the differentiation of steroidogenic progenitors into corticoid-producing cells.
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