Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism
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ABSTRACT:
PROVIDER: PRJNA785253 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17085900_1.fastq.gz | Fastqsanger.gz | |||
| SRR17085900_2.fastq.gz | Fastqsanger.gz | |||
| SRR17085901_1.fastq.gz | Fastqsanger.gz | |||
| SRR17085901_2.fastq.gz | Fastqsanger.gz | |||
| SRR17085902_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: The histone demethylase KDM1A is a multi-faceted regulator of critical developmental processes, including mesodermal and cardiac tube formation during mice gastrulation. The fine-tuning of KDM1A splicing has been linked to regulating the transcriptional program of excitable cells such as neurons. However, it is unknown whether modulating the expression of KDM1A isoforms is crucial for the specification and maintenance of cell identity of other cell types sensitive to electrical cues such as the cardiomyocytes. Objective: We investigated the role of ubKDM1A and KDM1A+2a ubiquitous splice variants during cardiomyogenesis and evaluated their impact on the regulation of cardiac differentiation in vitro. Methods and Results: We discovered a temporal modulation of ubKDM1A and KDM1A+2a isoform levels during human and mouse fetal cardiac development. Therefore, we generated human embryonic stem cells (hESCs) exclusively devoid of one or both isoforms and assessed their potential to derive cardiomyocytes. KDM1A depletion severely impaired cardiac differentiation. Conversely, KDM1A+2a-/- hESCs give rise to functional cardiomyocytes, displaying increased beating amplitude and frequency compared to wild-type cells. Transcriptomic profiling revealed that KDM1A-/- cardiomyocytes fail to activate an effective cardiac transcriptional program, while the depletion of KDM1A+2a enhances the expression of key cardiogenic markers. Notably, the impaired cardiac differentiation of KDM1A-/- cells can be rescued by re-expressing ubKDM1A or catalytically deficient ubKDM1A-K661A, but not by KDM1A+2a or KDM1A+2a-K661A. These data demonstrate a divergent role of the two KDM1A isoforms that is independent of their enzymatic activity. Through an exhaustive biochemical and genome-wide binding characterization, we excluded that the opposite ubKDM1A- and KDM1A+2a-mediated regulation of cardiac differentiation resides into differential substrate specificity, H3K4 demethylation efficiency, core-partners binding affinity, or alternative genome binding profiles. Conclusions: Our findings suggest the existence of a divergent scaffolding role of KDM1A splice variants during hESC differentiation into cardiomyocytes.
2022-07-01 | GSE189944 | GEO
Project description:The histone demethylase KDM1A is a multi-faceted regulator of vital developmental processes, including mesodermal and cardiac tube formation during gastrulation. However, it is unknown whether the fine-tuning of KDM1A splicing isoforms, already shown to regulate neuronal maturation, is crucial for the specification and maintenance of cell identity during cardiogenesis. Here, we discovered a temporal modulation of ubKDM1A and KDM1A+2a during human and mice fetal cardiac development and evaluated their impact on the regulation of cardiac differentiation. We revealed a severely impaired cardiac differentiation in KDM1A-/- hESCs that can be rescued by re-expressing ubKDM1A or catalytically impaired ubKDM1A-K661A, but not by KDM1A+2a or KDM1A+2a-K661A. Conversely, KDM1A+2a-/- hESCs give rise to functional cardiac cells, displaying increased beating amplitude and frequency and enhanced expression of critical cardiogenic markers. Our findings prove the existence of a divergent scaffolding role of KDM1A splice variants, independent of their enzymatic activity, during hESC differentiation into cardiac cells.
| S-EPMC9287196 | biostudies-literature
Project description:Mitochondria based priming of a stem/progenitor-like state involves fine-tuned repression of the master regulator of mitochondrial fission, Drp1, and drives carcinogen induced transformation in a keratinocyte model
2021-04-10 | GSE171772 | GEO
Project description:Ribosome profiling reveals the fine-tuned response of Escherichia coli to acid stress
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Project description:A fine-tuned regulation of Bmp2 by Nodal/TGFβ signalling induced lncRNA-Smad7
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Project description:The response to acidity is crucial for neutralophilic bacteria. Escherichia coli has a well characterized regulatory network to induce multiple defense mechanisms against excess of protons. Nevertheless, systemic studies of the transcriptional and translational reprogramming of E. coli to different acidic strengths have not yet been performed. Here, we used ribosome profiling and mRNA sequencing to determine the response of E. coli to pH 7.6, 5.8 and 4.4. Data were analyzed using the high-throughput HRIBO pipeline and previously undetected adaptations of E. coli to acid stress were found including up-regulation of glycerol catabolism and siderophore production, down-regulation of many membrane proteins and regulation by the transcriptional regulators YdeO, MhpR, IscR, and YdcI. Several examples of differential transcriptional and translational regulation of genes were identified as well as potential novel small open reading frames. These results expand the acid resistance network and provide new insights into the fine-tuned response of E. coli.
2023-09-28 | GSE219022 | GEO
Project description:The number of vertebrae is strictly defined for any given species1, and depends on the number of somites, which are periodically formed as perfectly matched cell masses during mid-embryogenesis, where the somite segmentation clock prescribes the timing2. The tempo of the clock is affected by surrounding condition, despite which the same number of somites is formed3, suggesting that the clock may be tunable to adapt to the environmental condition. Here, we demonstrate a tunability of the segmentation clock in the period depending on the level of Notch signaling that senses the surrounding information to adjust the number of somites and vertebrae precisely, in which we propose a mechanism of the clock with a feedback loop of Notch signaling by Notch-regulated ankyrin repeat protein (Nrarp). Disruption of Nrarp in mouse resulted in the loss of two vertebrae, due to 4-min extension of the period of the clock elicited by the up-regulation of Notch activity, whereas pharmacological diminishment of Notch activity shortens it by a few min. The Notch inhibitor rescues the phenotype of Nrarp knockout mice in the period. These results are comprehended by mathematical analyses, in which the period of the clock is fine-tuned by Notch activity that Nrarp adjusts. Overall, our results are the first to provide molecular evidence of fine-tuning of the segmentation clock that preserves the number of somites and vertebrae. Nrarp mutant mouse which have LacZ gene instead of Nrarp coding region was generated by homologous recombinant. Fragnant female heterozygous mutant mice, mated with heterozygous mutant male, were dissected at embryonic day 10.5 (E10.5). 12 PSMs were collected in each genotype to extract total RNA.
2010-10-01 | E-GEOD-18419 | biostudies-arrayexpress
Project description:KDM1A requires an adaptor protein with specific DNA-binding activity to recognize chromatin sequence. We constructed HepG2 cells stably overexpressing KDM1A-Flag tag using lentivirus. We performed Co-IP with Flag-gel and we used LC-MS to determine the immunoprecipitates of KDM1A.
2023-05-19 | PXD043284 |
Project description:The number of vertebrae is strictly defined for any given species1, and depends on the number of somites, which are periodically formed as perfectly matched cell masses during mid-embryogenesis, where the somite segmentation clock prescribes the timing2. The tempo of the clock is affected by surrounding condition, despite which the same number of somites is formed3, suggesting that the clock may be tunable to adapt to the environmental condition. Here, we demonstrate a tunability of the segmentation clock in the period depending on the level of Notch signaling that senses the surrounding information to adjust the number of somites and vertebrae precisely, in which we propose a mechanism of the clock with a feedback loop of Notch signaling by Notch-regulated ankyrin repeat protein (Nrarp). Disruption of Nrarp in mouse resulted in the loss of two vertebrae, due to 4-min extension of the period of the clock elicited by the up-regulation of Notch activity, whereas pharmacological diminishment of Notch activity shortens it by a few min. The Notch inhibitor rescues the phenotype of Nrarp knockout mice in the period. These results are comprehended by mathematical analyses, in which the period of the clock is fine-tuned by Notch activity that Nrarp adjusts. Overall, our results are the first to provide molecular evidence of fine-tuning of the segmentation clock that preserves the number of somites and vertebrae.
2010-10-01 | GSE18419 | GEO
Project description:The purpose of this study was to chacterise the effect of KDM1A knocking down on genome-wide gene expression in human NSCLC cells in vivo. Affymetrix human transcriptome array 2.0 was used to profile the transcriptome of xenograft tumors derived from PC9 cells stably expressing either ShRNA KDM1A or ShRNA control. These cells were subcutanously injected into the right axillary of the mouse, and allowd to grow for 5 weeks to form xenograft tumors. Although KDM1A is up-regulated in NSCLC, but key genes and pathways regulated by KDM1A was not well-understood in NSCLC. Using this approach, we have shown that KDM1A repressed or activated a distinctive set of pathways and key target genes in vivo. This first comprehesive study of transciptome profile upon KDM1A koncking-down in vivo highlights the distinctive pathways regulated by KDM1A during NSCLC tumorigenesis, and it will help to identify new therapeutic targets for NSCLC treatment. Xenograft tumors derived from two cell lines: PC9 cells stably expressing ShRNA KDM1A or ShRNA control. We extracted total RNA from 3 independent xenograft tumors per cell line.
2016-07-27 | E-GEOD-71358 | biostudies-arrayexpress