Nuclear control of mitochondrial function mediated by Zbtb11
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ABSTRACT:
PROVIDER: PRJNA515041 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8440270.fastq.gz | Fastqsanger.gz | |||
| SRR8440280_1.fastq.gz | Fastqsanger.gz | |||
| SRR8440280_2.fastq.gz | Fastqsanger.gz | |||
| SRR8440271.fastq.gz | Fastqsanger.gz | |||
| SRR8440281_1.fastq.gz | Fastqsanger.gz |
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Project description:Zbtb11 is an uncharacterised transcription factor that is conserved in vertebrates. Mutations in its human gene cause a form of inherited intellectual disablity, while in zebrafish Zbtb11 mutations lead to impaired hematopoesis and neruonal development. We used a combination of functional genomics approaches to determine its functions. To determine the genomic Zbtb11 binding locations, we carried out ChIP-seq using FLAG antibodies in a cell line with the endogenous Zbtb11 N-terminally tagged with FLAG (Zbtb11 FLAG/FLAG), as well as using an anti-Zbtb11 antibody in a wild type line. To determine the genes regulated by Zbtb11 we generated an inducible KO line (Zbtb11 lox/lox, Rosa26 ERt2-Cre) that allows the rapid depletion of Zbtb11 upon treatment with 4-hydroxytamoxyfen (4OHT). We treated Zbtb11 lox/lox, Rosa26 ERt2-Cre cells either with 4OHT (Zbtb11 KO) or ethanol (EtOH) as control, and subsequently performed directional RNA-seq from samples collected 48 hours post-treatment. As control for the effect of 4OHT on gene expression, we also compared Zbtb11 KO cells to wild type cells treated with 4OHT. The two ChIP-seq approaches showed very good overlap and allowed us to generate a set of high-confidence Zbtb11 binding sites common to both peak sets. We found Zbtb11 preferentially binds to a subset of house-keeping genes among which genes encoding proteins with mitochondrial functions are enriched. Upon Zbtb11 deletion, 154 genes changed expression 48 hours later, the vast majority of them down-regulated. Integration of ChIP-seq and RNA-seq data allowed us to identify the genes directly regulated by Zbtb11, and these were significantly enriched in genes with mitochondrial functions, with respiratory complex I and mitoribosome biogenesis being the overrepresented pathways. Subsequent biochemical experiments confirmed Zbtb11 is required for respiratory complex I assembly and for mitochondrial translation. In agreement with these findings Zbtb11 KO led to impaired respiration, proliferation arrest and cell death.
2020-01-14 | GSE125047 | GEO
Project description:Zbtb11 is a transcription factor conserved in vertebrates. Mutations in its human gene cause a form of inherited intellectual disablity, while in zebrafish Zbtb11 mutations lead to impaired hematopoesis and neruonal development. To determine the genes regulated by Zbtb11 we generated an inducible KO ES cell line (Zbtb11 lox/lox, Rosa26 ERt2-Cre) that allows the rapid depletion of Zbtb11 upon treatment with 4-hydroxytamoxyfen (4OHT). We subsequently performed RNA-seq in Zbtb11 KO and control cells to determine differentially expressed genes. Upon Zbtb11 deletion 310 genes changed expression. Integration of the RNA-seq data with Zbtb11 ChIP-seq data (GEO series GSE125047) allowed us to distinguish between genes directly regulated by Zbtb11 and indirect changes. 204 differentially expressed genes were bound by Zbtb11, while 106 did not have Zbtb11 binding sites. Directly regulated genes were significantly enriched in genes with mitochondrial functions, while indirectly controlled genes were enriched for p53 targets. In agreement with these findings Zbtb11 KO led to impaired respiration, proliferation arrest and cell death.
2022-12-31 | GSE130292 | GEO
Project description:Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells.
2020-01-23 | E-MTAB-8673 | biostudies-arrayexpress
Project description:Mitochondrial associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples described, we set out to identify RBPs that post-transcriptionally regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our analysis of RNA-target sets of RBPs made available by ENCODE identified several RBPs with a preference for binding NEMmRNAs, of which we selected LARP4, a La RBP family member, for further study. We show that LARP4’s RNA-target set is particularly enriched in mRNAs that encode for respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. CRISPR knockout cells in conjunction with quantitative proteomics show that protein levels of RCCPs and MRPs are significantly reduced upon loss of LARP4. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and this phenotype is ameliorated by LARP4 re-expression. Our findings shed light onto a novel function for LARP4 as an RBP that binds to NEMmRNAs to promote mitochondrial respiratory function.
2024-03-11 | GSE193134 | GEO
Project description:Control of microRNA expression by mitochondrial function
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Project description:In this study, we used mRNA-Seq and functional assays to investigate the transcriptomic and cellular responses to nuclear-mitochondrial genetic mismatches using the xenomitochondrial cybrid panel. RNA-Seq revealed a remarkable reprogramming of nuclear gene expression in response to variation in the mitochondrial genome that involved adaptive changes in cellular metabolism and cell cycle regulation. Unexpectedly, we found that nuclear-mitochondrial mismatch elicits a strong interferon-mediated cellular response
2018-11-01 | GSE113340 | GEO
Project description:ZBTB11 binding genes in NCI-H1299
2023-12-21 | GSE206958 | GEO
Project description:Zbtb11 is a conserved transcription factor mutated in families with hereditary intellectual disability. Its precise molecular and cellular functions are currently unknown, precluding our understanding of the aetiology of this disease. Using a combination of functional genomics, genetic and biochemical approaches, here we show that Zbtb11 plays essential roles in maintaining the homeostasis of mitochondrial function. Mechanistically, we find Zbtb11 facilitates the recruitment of nuclear respiratory factor 2 (NRF-2) to its target promoters, activating a subset of nuclear genes with roles in the biogenesis of respiratory complex I and the mitoribosome. Genetic inactivation of Zbtb11 resulted in a severe complex I assembly defect, impaired mitochondrial respiration, mitochondrial depolarisation, and ultimately proliferation arrest and cell death. Experimental modelling of the pathogenic human mutations showed these have a destabilising effect on the protein, resulting in reduced Zbtb11 dosage, downregulation of its target genes, and impaired complex I biogenesis. Our study establishes Zbtb11 as an essential mitochondrial regulator, improves our understanding of the transcriptional mechanisms of nuclear control over mitochondria, and may help to understand the aetiology of Zbtb11-associated intellectual disability.
| S-EPMC7596099 | biostudies-literature
Project description:Aims Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive fibro-fatty replacement of the myocardium, arrhythmias, and sudden death. While myocardial degeneration and fibro-fatty replacement occurs in specific locations, the underlying molecular changes remain poorly characterized. Here we aim to delineate local changes in gene expression to help identify new genes or pathways that are relevant for specific remodelling processes occurring during ACM. Methods and Results Using Tomo-Seq, a genome-wide transcriptional profiling with high spatial resolution, we created a transmural epicardial to endocardial gene expression atlas of an explanted ACM heart to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing we revealed BTB (broad-complex, tramtrack, bric-à-brac) domain containing 11 (ZBTB11) to be specifically enriched at sites of active fibrofatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be enriched in cardiomyocytes flanking fibrofatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 in iPS-derived cardiomyocytes showed ZBTB11 to function as a potent inducer of cardiomyocyte atrophy. Conclusion By combining spatial transcriptomics with classical histological approaches we identified gene expression changes underlying local remodelling responses in ACM. In doing so we found ZBTB11 to function as a relevant driver of cardiomyocyte atrophy. These data show the power of Tomo-Seq to unveil new molecular mechanisms and indicate ZBTB11 as a potential new target for cardiomyopathy.
2021-05-22 | GSE114770 | GEO
Project description:Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand proteins encoded by nuclear genome. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 targets methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), the rate-limiting enzyme for nuclear NAD+ synthesis. Hepatic LSD1 knockout reduces NAD+-dependent Sirt1 and Sirt7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABP and PGC-1, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
2021-02-01 | GSE145089 | GEO