Effects of the histone demethylase LSD1/KDM1A on the gene expression program of murine hematopoietic progenitor cells.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE66074 | GEO | 2015/02/20
SECONDARY ACCESSION(S): PRJNA275830
REPOSITORIES: GEO
Similar Datasets
Project description:We established transgenic mice overexpressing the histone demethyase LSD1/KDM1A under the control of Sca-1 promoter and investigated the global changes in gene expression in hematopoietic progenitor cells using a microarray- based approach. We isolated mRNA from Sca-1-positive hematopoietic progenitor cells from two transgenic mice, Line 6 and Line 3, and subjected them to gene expression analysis using an Affimetrix GeneChip Array.
2015-02-20 | E-GEOD-66074 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE34672: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [Illumina HumanHT-12 gene expression array] GSE34725: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [ChIP-Seq] Refer to individual Series
2012-03-14 | E-GEOD-34726 | biostudies-arrayexpress
Project description:Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on LysM-bM-^@M-^I4 or LysM-bM-^@M-^I9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages. Our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation. To identify direct target genes of Lsd1 in myeloid cells we mapped global occupancy of Lsd1 in 32D granuolocytic progenitor cells and compared H3K4me1/me2/me3 and H3K27ac histone modifications in Lsd1fl/fl (wild type) vs. Lsd1fl/f Mx1Cre (knockout) Gr1dim Mac1 granuolocytic progenitor cells.
2013-06-25 | E-GEOD-40440 | biostudies-arrayexpress
Project description:Here we describe that lysine-specific demethylase 1 (Lsd1/KDM1a), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/K9), is an indispensible epigenetic governor of hematopoietic differentiation. Integrative genomic analysis in primary hematopoietic cells, combining global occupancy of Lsd1, genome-wide analysis of its histone substrates H3K4 mono- and di-methylation and gene expression profiling, reveals that Lsd1 represses hematopoietic stem and progenitor cell (HSPC) gene expression programs during hematopoietic differentiation. We found that Lsd1 function was not restricted to transcription start sites, but is also critical at enhancers. Loss of Lsd1 at these sites was associated with increased H3K4me1 and H3K4me2 methylation levels on HSPC genes and their derepression. Failure to fully silence HSPC genes compromised differentiation of hematopoietic stem cells and mature blood cell lineages. Our data indicate that Lsd1-mediated concurrent repression of enhancer and promoter activity of stem and progenitor cell genes is a pivotal epigenetic mechanism required for proper hematopoietic maturation.
2013-06-25 | GSE40440 | GEO
Project description:Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogues active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia which may be selectively targeted to therapeutic effect. To investigate the genetic program regulated by KDM1A in murine MLL-AF9 AML cells enriched for LSCs, we compared the transcriptome of KIT+Gr1+ control and Kdm1a KD cells using exon arrays soon after initiation of KD. At this time, there was no immunophenotypic evidence of differentiation in Kdm1a KD cells. Exonic expression values were condensed into gene-level expression summaries, which represent the mean expression value of the probe sets targeting the length of a given protein coding gene. Three separate samples from two different animals were used. Kdm1a KD samples were compared with control samples. Total six arrays.
2012-03-28 | E-GEOD-36347 | biostudies-arrayexpress
Project description:Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC primary samples, KDM1A expression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype (e.g., the activation of a collateral mitochondrial metabolic pathway independent from succinate-CoA ligase GDP-forming subunit beta 2, expressions of brush border’s protein villin, and ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) suggesting a key role of KDM1A in cell metabolism. Also, KDM1A silencing resulted in a 3-fold increase in the expression of miR-506-3p. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A plays a key role in CRC progression and therefore it represents a promising epigenetic target to prevent tumor relapse.
2023-07-20 | PXD037259 | Pride
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:Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogues active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia which may be selectively targeted to therapeutic effect. To investigate the effects of Kdm1a KD on histone modifications, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq) in control and Kdm1a KD MLL-AF9 AML cells for dimethyl-H3K4 and dimethyl-H3K9, as well as for trimethyl-H3K4 and trimethyl-H3K9. Dimethyl-H3K4 and dimethyl-H3K9 are targeted for demethylation by KDM1A. For each of these histone modifications, we compared the mean ChIP-Seq signal across and around protein coding genes bound by the MLL-AF9 oncoprotein (Bernt et al., 2011) with the mean signal from genes not bound by MLL-AF9 expressed at high, middle or low levels.
2012-03-28 | E-GEOD-36346 | biostudies-arrayexpress
Project description:Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to ?-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.
| S-EPMC3824007 | biostudies-other
Project description:Lysine-specific demethylase 1 (LSD1) catalyzes the demethylation at H3K4 and H3K9 and is well- known for its role in decommissioning enhancers during mouse embryonic stem cell (ESC) differentiation. However, its role at gene promoters remains poorly understood in ESCs despite their widespread presence at these sites. Here, we report that LSD1 promotes RNA Polymerase II (RNAPII) pausing, a rate-limiting step in transcription regulation, in ESCs. We found that the knockdown of LSD1 preferentially affects genes with higher RNAPII pausing than those with lower pausing. We show that LSD1 knockdown leads to the global reduction in RNAPII pausing and most significantly on the genes bound by LSD1. Next, we demonstrate that the co-localization of LSD1 and MYC, a factor known to regulate pause-release, is associated with the enrichment of other RNAPII pausing factors. Finally, we found that genes co-occupied by LSD1 and MYC are significantly enriched for housekeeping genes that are involved in metabolic processes and depleted of transcription factors compared to those bound only by LSD1. Our integrative analysis reveals a pleiotropic role of LSD1 in promoting RNAPII pausing and in regulating housekeeping programs besides its known role in regulating cell identity programs.
2022-08-16 | GSE173089 | GEO