Genome-wide analysis of altered gene expression pattern upon Atad3a deletion in mouse bone marrow lineage negative progenitor cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71861 | GEO | 2018/08/05
REPOSITORIES: GEO
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Project description:From our previous data, we found that loss of ATAD3A gene expression in breast cancer cells results in loss of cell motility in vitro and metastasis in vivo. To obtain a better understanding of oncogenic pathway of ATAD3A, we have established the stable ATAD3A knockdown MDA-MB-231 cells using lentiviral strategy. We used the whole genome microarrays to detail the global programme of gene expression after depleting of ATAD3A and identified distinct classes of up or down-regulated metastmir associated with breast cancer cells migration Total RNA was extracted from ATAD3A stable knockdown cells (shATAD3A) and the control cells (shGFP). The labeled RNA was hybridized on U133 plus 2.0 Array. To identify altered gene expression patterns with or without ATAD3A expression, we compared average mRNA expression levels between the ATAD3A knockdown and control MDA-MB-231 cells.
2015-03-01 | E-GEOD-56084 | biostudies-arrayexpress
Project description:Background: Aortic aneurysm and dissection (AAD) is a fatal vascular emergency with limited mechanism-based therapies. The mitochondrial AAA⁺ ATPase ATAD3A, enriched at organelle contact sites, has been implicated in mitochondrial signaling, but its role in AAD remains unclear. Methods: AAD was induced in wild-type, ATAD3A knock-in (ATAD3A-KI), and vascular smooth muscle cell (VSMC)-specific knockdown (sh-ATAD3A) mice by 3-week β-aminopropionitrile monofumarate (BAPN) intake or 28-day angiotensin II (AngII) infusion via osmotic minipumps. Aortic dilatation, dissection incidence, rupture-related mortality, and histology were assessed. VSMCs were stimulated with AngII in vitro. Mitochondrial function was evaluated using Seahorse bioenergetics, membrane potential assay, and Ca²⁺ imaging. ATAD3A-dihydrolipoamide s-succinyltransferase (DLST) interaction was examined by co-immunoprecipitation. Pharmacological modulation was performed with the copper chelator tetrathiomolybdate (TTM) and the lipoylation inhibitor Devimistat. Results: ATAD3A expression was upregulated in human thoracic aortic dissection samples and in BAPN-treated mouse aortas, with early downregulation then late upregulation in VSMCs. Systemic ATAD3A overexpression mitigated BAPN- and AngII-induced aortic dilatation, reduced dilation incidence, and improved survival, whereas VSMC-specific knockdown accelerated vascular pathology. Mechanistically, ATAD3A overexpression reduced mitochondria-lysosome contacts, limited mitochondrial Ca²⁺ influx, and suppressed the FDXR/FDX1/LIAS lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis, thereby preserving VSMC viability and delaying AAD progression. Pharmacological inhibition of cuproptosis using TTM or Devimistat attenuated disease severity in vivo. Conclusions: ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca²⁺ influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD.
2026-06-20 | GSE329337 | GEO
Project description:From our previous data, we found that loss of ATAD3A gene expression in breast cancer cells results in loss of cell motility in vitro and metastasis in vivo. To obtain a better understanding of oncogenic pathway of ATAD3A, we have established the stable ATAD3A knockdown MDA-MB-231 cells using lentiviral strategy. We used the whole genome microarrays to detail the global programme of gene expression after depleting of ATAD3A and identified distinct classes of up or down-regulated metastmir associated with breast cancer cells migration
2015-03-01 | GSE56084 | GEO
Project description:Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATAD3A, a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.
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Project description:These are raw mass spectrometry data discussed in our paper: “The LMO2-LDB1-TAL1 complex regulates transcription networks in AML”, where we implicate this multisubunit complex as a key regulator of leukemia cell transcription. The key method was affinity purification followed by tandem mass spectrometry. The LDB1 and LMO2 proteins were FLAG tagged and encoding cDNAs were cloned into lentiviral expression vectors allowing transduction of leukemia cells. Protein purification and MS/MS are described below.
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Project description:The ATPase Family AAA Domain Containing 3A (ATAD3A) is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knockout (Atad3 nKO) mouse model, which developed a severe encephalopathy by 5 months of age. Pre-symptomatic mice showed aberrant mitochondrial cristae morphogenesis in the cortex as early as 2 months. Using a multi-omics approach in the CNS of 2-3-month-old mice, we found early alterations in the organelle membrane structure. We also showed that human ATAD3A associates with different components of the inner membrane, including: OXPHOS complex I, Letm1 and prohibitin complexes. Stochastic Optical Reconstruction Microscopy (STORM) showed that ATAD3A is regularly distributed along the inner mitochondrial membrane, suggesting a critical structural role in inner mitochondrial membrane and its organization, most likely in an ATPase-dependent manner.
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Project description:Notch signaling primarily determines T-cell fate. However, the molecular mechanisms underlying the maintenance of T-lineage potential in pre-thymic progenitors remain unclear. Here, we established two Ebf1-deficient pro-B cell lines, with and without T-lineage potential. The latter expressed lower levels of Lmo2; their potential was restored via ectopic expression of Lmo2. Conversely, the CRISPR/Cas9-mediated deletion of Lmo2 resulted in the loss of the T-lineage potential. Introduction of Bcl2 rescued massive cell death of Notch-stimulated pro-B cells without efficient LMO2-driven Bcl11a expression but was not sufficient to retain their T-lineage potential. Pro-B cells without T-lineage potential failed to activate Tcf7 due to DNA methylation; Tcf7 transduction restored this capacity. Moreover, direct binding of LMO2 to the Bcl11a and Tcf7 loci was observed. Altogether, our results highlight LMO2 as a crucial player in the survival and maintenance of T-lineage potential in T-cell progenitors via the regulation of the expression of Bcl11a and Tcf7.
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2017-11-01 | GSE99938 | GEO
Project description:Early B cell factor 1 (EBF1) is one of the key transcription factors required for orchestrating B-cell lineage development. Although studies have shown that Ebf1 haploinsufficiency is involved in the development of leukemia, no study has been conducted that characterizes the global effect of Ebf1 heterozygosity on the proteome of pro-B lymphocytes. Here, we employ both DIA (Data Independent Acquisition) and shotgun DDA (Data Dependent Acquisition) workflows for profiling proteins that are differently expressed between Ebf1+/+ and Ebf1+/- cells. Both DDA and DIA were able to reveal the downregulation of the EBF1 transcription factor in Ebf1+/- pro-B lymphocytes. Further examination of differentially expressed proteins by DIA revealed that, similar to EBF1, the expression of other B-cell lineage regulators, such as TCF3 and Pax5, is also down-regulated in Ebf1 heterozygous cells. Functional DIA analysis of differentially expressed proteins showed that EBF1 heterozygosity resulted in the deregulation of at least 8 transcription factors involved in lymphopoiesis, and to the deregulation of key proteins playing crucial roles in survival, development and differentiation of pro-B lymphocytes.
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