Differential Notch target genes expression profile upon HDAC3 loss-of-function.
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ABSTRACT:
PROVIDER: PRJNA416379 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6236480.fastq.gz | Fastqsanger.gz | |||
| SRR6236481.fastq.gz | Fastqsanger.gz | |||
| SRR6236482.fastq.gz | Fastqsanger.gz | |||
| SRR6236473.fastq.gz | Fastqsanger.gz | |||
| SRR6236483.fastq.gz | Fastqsanger.gz |
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Project description:The Notch signaling pathway regulates several differentiation and developmental processes in both pre- and post-natal life and its aberrant regulation leads to diseases, including cancer. Here, we investigated the role of histone deacetylase 3 (HDAC3) on the regulation of the Notch-dependent gene expression program in mouse pre-T (Beko) cells. We first defined Notch target genes as those genes that are downregulated upon inhibition of the Notch pathway using DAPT, a gamma-secretase inhibitor (GSI). Subsequently, we investigated the role of HDAC3 in the regulation of Notch target genes by shRNA- and pharmacologically (apicidin)-mediated loss-of-function of HDAC3.
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Project description:Differential Notch target genes expression profile upon GSI washout.
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Project description:The Notch signaling pathway regulates several differentiation and developmental processes in both pre- and post-natal life and its aberrant regulation leads to diseases, including cancer. Here, we investigated the genome-wide distribution of the transcription factor RBPJ and the differential regulation of H3K27ac upon pharmacological inhibition of histone deacetylase 3 (HDAC3) with apicidin in mouse pre-T (Beko) cells.
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Project description:Histone deacetylase 3 (Hdac3) is the enzymatic component of transcriptional repression complexes recruited by the nuclear hormone receptors. Inactivation of Hdac3 in cancer cell lines triggered apoptosis, and removal of Hdac3 in the germ-line of mice caused embryonic lethality. Therefore, we conditionally deleted the Hdac3 allele in the mouse liver. These mice developed hepatomegaly, which was the result of hepatocyte hypertrophy, and these morphological changes coincided with significant imbalances between carbohydrate and lipid metabolism. Loss of Hdac3 triggered changes in gene expression consistent with inactivation of repression mediated by nuclear hormone receptors. Mechanistically, loss of Hdac3 increased the levels of Pparγ2, and treatment of these mice with a Pparγ antagonist partially reversed the lipid accumulation in the liver. In addition, gene expression analysis identified mTOR (mammalian target of rapamycin) signaling as being activated by deletion of Hdac3, and inhibition by rapamycin also affected the accumulation of neutral lipids in the Hdac3-null livers. Thus, Hdac3 has a key role in regulation of multiple signaling pathways in the liver, and deletion of Hdac3 disrupts normal metabolic homeostasis. Keywords: Genetic knockout of Hdac3 specifically in liver, and RNA analyzed from postnatal day 17 or 28 livers for transcriptional changes related to the given phenotypes
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Project description:Small cell lung cancer (SCLC) is an aggressive malignancy, with most patients presenting with prognostically poor extensive-stage disease. Limited progress in standard care stresses the urgent need for novel therapies. Radiotherapy offers some survival benefit for select SCLC patients but could be enhanced with radiosensitizers. Here, we identify HDAC3 as a novel radiosensitizing target in SCLC using a CRISPR knockout screen and demonstrate its efficacy and mechanism. SBC5 cells were transduced with a custom EpiDrug sgRNA library and treated with ionizing radiation (IR). Cells were collected and sequenced at multiple timepoints to identify radiosensitizing genes. To validate this target, HDAC3 functional loss was generated by genetic knockdown (KD) and RGFP966 inhibition in several SCLC cell lines. HDAC3 KD and RGFP966 inhibition increased radiosensitivity, as shown by cell viability (dose[1]modification factor [DMF]10 = 1.14-1.69) and clonogenic assays (DMF10 = 1.16-1.41). We evaluated changes in chromatin accessibility by ATAC-seq, and IR-induced DNA damage and repair using γH2AX foci detection and double-strand break (DSB) repair assays. Cells with HDAC3 functional loss demonstrated increased chromatin accessibility which was associated with more IR-induced DNA DSBs, and impaired DSB repair function leading to persisting DNA damage. In SCLC xenograft models, HDAC3 KD or RGFP966, combined with IR, enhanced radiosensitivity and achieved significant tumor growth inhibition. Taken together, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increases the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC.
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Project description:The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes much milder changes in far fewer genes. The abnormal gene expression is cardiomyocyte-autonomous and can be rescued by an enzyme-dead HDAC3 mutant but not by an HDAC3 mutant (Δ33-70) that lacks interaction with the nuclear-envelope protein lamina-associated polypeptide 2β (LAP2β). Tethering LAP2β to the HDAC3 Δ33-70 mutant restored its ability to rescue gene expression. Finally, HDAC3 depletion, not loss of HDAC3 enzymatic activity, exacerbates cardiac contractile functions upon aortic constriction. These results suggest that the cardiac function of HDAC3 in adults is not attributable to its enzyme activity but to its nuclear envelope tethering action, which has implications for understanding the cardioprotective effects of HDIs.
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Project description:Autism spectrum disorders (ASDs) are a neurodevelopmental disorder characterized by impairments in social interactions and stereotyped behaviors. While ASD has a strong genetic background, environmental factors including toxins, pesticides, infection and drugs are also known to confer autism susceptibility, likely by inducing epigenetic changes. Exposure to Valproic acid (VPA), a drug for epilepsy and bipolar disorders, during pregnancy is highly associated with the risk of ASD children. In rodents, in utero VPA exposure can precipitate behavioral phenotypes related to ASD in the offspring. Since VPA is an inhibitor of histone deacethytransferase (HDAC) activity, it thought to cause ASD with epigenetic modification. However, the core mechanism by which prenatal VPA exposure causes onset of ASD is still not fully uncovered. Here we revealed that prenatal VPA exposure strongly influences development of vasoactive intestinal peptide (VIP) - positive neurons, a subtype of cortical GABAergic interneurons. The number of VIP+ interneurons was severely reduced in somatosensory area of VPA-exposed ASD animals. We then found that the reduction in VIP+ interneurons is caused by the inhibition of HDAC3 activity upon prenatal VPA exposure. Importantly, prenatal HDAC3 inhibition caused not only the selective reduction in VIP+ interneurons but also the ASD-like behaviors in mice. We then demonstrated that the HDAC3 inhibition aberrantly activates Notch signaling, which influences the cell fate determination of VIP+ interneuron progenitors in caudal ganglionic eminence. Thus, this study uncovers the mechanism by which specific HDAC inhibition during development influences a specific type of GABAergic interneurons in the ASD model. The findings provide a novel insight into the understanding of ASD pathophysiology.
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Project description:Analysis of gene expression profiles upon PFKFB3 under- or overexpression during inhibition or activation of notch signaling. With this experiment we aimed to identify whether alterations in PFKFB3 could influence the expression pattern of angiogenic genes in conditions that favor a tip- or stalk cell gene signature. Total RNA was collected of human umbilical vein endothelial cells either under- or overexpressing PFKFB3 and/ or have inhibited or activated notch signaling respectively. Cells were harvested 48h after manipulation of PFKFB3 and notch levels.
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