LSD1 induces H3K9 demethylation to promote adipogenesis in Thyroid associated ophthalmopathy
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ABSTRACT:
PROVIDER: PRJNA1206462 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31893369_1.fastq.gz | Fastqsanger.gz | |||
| SRR31893369_2.fastq.gz | Fastqsanger.gz | |||
| SRR31893370_1.fastq.gz | Fastqsanger.gz | |||
| SRR31893370_2.fastq.gz | Fastqsanger.gz | |||
| SRR31893371_1.fastq.gz | Fastqsanger.gz |
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Project description:Thyroid-associated ophthalmopathy (TAO) is an autoimmune orbital disease, multiple factors including genetic and immune factors, contribute to TAO progression, thus there is no available drugs targeting TAO. Here, we investigated the underlying mechanism of adipogenesis in TAO from an epigenetic point, we found lysine specific demethylase (LSD1) was highly expressed in TAO compared with non-TAO, and knocking down LSD1 led to decreased expression of adipocyte markers and inflammatory genes. Mechanically, LSD1 removed the H3K9me2 mark on the promoter of adipocyte genes, activating their expression. Finally, pargyline, an inhibitor of LSD1, inhibited adpogenesis in a dose-dependent manner. Taken together, our study revealed a novel mechanism of adipocyte differentiation during TAO progression, and demonstrated LSD1 is a potential anti-adipogenesis target in TAO.
2025-05-08 | GSE285862 | GEO
Project description:During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development. In order to find some LSD1+8a regulated genes at differentiated SH-SY5Y cell lines, we infected SH-SY5Y with control or LSD1+8a shRNA, then induced differentiation with RA and BDNF, (Retinoic acid (RA) (Sigma) was added at a final concentration of 10 μM the next day after plating. After 4 days, the cells were washed three times with PBS and incubated with 50 ng/mL of Brain Derived Neural Factor (BDNF) (Millipore) in serum-free medium for 3 days), we extracted RNA from BDNF induced SH-SY5Y cells for expression analysis.Duplicates were included for Affymetrix Human transcriptome version 2 array.
2015-06-05 | E-GEOD-63097 | biostudies-arrayexpress
Project description:During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development.
2015-06-05 | GSE63097 | GEO
Project description:During brain development, histone-modifying enzymes play an important role by orchestrating transcriptional programs that regulate neuronal maturation. Lysine-Specific Demethylase 1 (LSD1, also named as KDM1A) functions as a transcriptional repressor by removing methyl groups at lysine 4 of histone H3 (H3K4). In neurons, alternative splicing can include an additional exon (exon E8a) within LSD1 transcripts, generating a LSD1+8a neuro-specific isoform. We here report that LSD1+8a isoform does not have the intrinsic ability to demethylate H3K4. LSD1+8a functions as a co-activator on its target genes by removing H3K9 repressive histone marks. We identify the supervillin protein (SVIL) as a LSD1+8a interacting partner and demonstrate that SVIL protein regulates neuronal maturation by controlling LSD1+8a mediated H3K9 demethylation. Thus, our results show that alternative splicing provides a genius mechanism by which LSD1 isoforms can acquire a dual specificity (H3K9 vs H3K4) and therefore differentially control specific gene expression patterns during brain development.
2015-06-05 | GSE58258 | GEO
Project description:Histone H3 lysine-9 methylation (H3K9me) is essential for retinoblastoma protein (RB)-mediated heterochromatin formation, epigenetic silencing of S-phase genes and permanent cell cycle arrest or cellular senescence. Besides as an H3K4me demethylase, lysine-specific demethylase 1 (LSD1) has also been shown to promote H3K9 demethylation. However, it is unclear whether LSD1 plays any roles in regulating cell cycle entry and senescence. Here we demonstrate that genetic depletion or pharmacological inhibition of LSD1 triggers G1 arrest and cellular senescence. Genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveal that the binding sites of LSD1 significantly overlaps with those bound by the S-phase gene transcription factor E2F1. Gene ontology (GO) analysis demonstrates that a large portion of E2F1 and LSD1 co-targeted genes are involved in cell cycle and proliferation. Further analyses show that depletion of LSD1 not only inhibits expression of the LSD1-E2F1 co-target genes, but also decreases the level of H3K9me2, but not H3K4me2 in those loci. Furthermore, the enzymatic activity of LSD1 is essential for H3K9me2 demethylation at cell cycle gene loci. Notably, co-treatment of chemotherapeutic agent camptothecin (CPT) enhanced LSD1 inhibitor-induced senescence and growth inhibition of cancer cells in vitro and in mice. Our data reveal LSD1 as a molecular rheostat regulating selective H3K9 demethylation at cell cycle gene loci, thereby representing a key event in oncogenesis and a viable target for cancer therapy.
2017-01-29 | GSE77448 | GEO
Project description:TET1 promotes adipogenesis through DNA demethylation
| PRJNA604385 | ENA
Project description:Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite a large progress on the transcriptional network of PPARγ, the epigenetic regulation associated with histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly binds to PPARγ through the CoRNR box 2 and represses the transcription activity and adipogenic potential of PPARγ. Upon CACUL1 depletion, less SIRT1 and more LSD1 was recruited to the PPARγ-responsive gene promoter, leading to the increased histone H3K9 acetylation and decreased H3K9 methylation for PPARγ activation during adipogenesis of 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA-seq supported the repressive role of CACUL1 in PPARγ activation and fat accumulation. Finally, we confirmed the CACUL1 function in human adipose-derived stem cells. Overall, our data suggest that CACUL1 tightly regulates PPARγ signaling through the mutual opposition between SIRT1 and LSD1, providing additional insight into its use for anti-obesity treatment.
2017-10-17 | GSE105055 | GEO
Project description:TET1 promotes adipogenesis through DNA demethylation [RNA-seq]
| PRJNA604384 | ENA
Project description:Lysine Specific Demethylase 1 (LSD1) removes mono- and dimethyl groups from lysine 4 of histone H3 (H3K4) or H3K9, resulting in repressive or activating (respectively) transcriptional histone marks. The mechanisms that control the balance between these two antagonist activities are not understood. We here show that LSD1 and the orphan nuclear receptor estrogen-related receptor α (ERRα) display commonly activated genes. Transcriptional activation by LSD1 and ERRα involves H3K9 demethylation at the transcriptional start site (TSS). Strikingly, ERRα is sufficient to induce LSD1 to demethylate H3K9 in vitro. The relevance of this mechanism is highlighted by functional data. LSD1 and ERRα coregulate several target genes involved in cell migration, including the MMP1 matrix metallo-protease, also activated through H3K9 demethylation at the TSS. Depletion of LSD1 or ERRα reduces the cellular capacity to invade the extracellular matrix, a phenomenon that is rescued by MMP1 reexpression. Altogether our results identify a regulatory network involving a direct switch in the biochemical activities of a histone demethylase, leading to increased cell invasion.
| S-EPMC5393192 | biostudies-literature
Project description:Protein kinase A phosphorylates proteins including histone H3 lysine 9 (H3K9) demethylase JMJD1A to facilitate beige adipogenesis upon β-adrenergic receptor (β-AR) activation, however, phosphatase(s) that antagonizes phosphorylation to inhibit beige adipogenesis is incompletely understood. Here we show that MYPT1-PP1β is a phosphatase that negatively regulates beige adipogenesis via dephosphorylation of pS265-JMJD1A and myosin regulatory light chain. Upon β-AR activation, MYPT1-PP1β is inhibited via T694 phosphorylation of MYPT1, facilitating phosphorylation of JMJD1A and beige adipogenesis under cold stress. Depletion of MYPT1-PP1β induces Ucp1 by orchestrating JMJD1A-mediated H3K9 demethylation and actomyosin-tension mediated YAP/TAZ activation. This induction of Ucp1 is abrogated in adipocytes expressing catalytically dead JMJD1A mutant, indicating that the coordinated epigenetic and transcriptional mechanisms are essential for beige adipogenesis. We also show that preadipocytes specific Mypt1 deficient mice exhibit higher cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice confirming its role at animal levels.
2022-09-26 | PXD031210 | JPOST Repository