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LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers [BrU-Seq]

ABSTRACT: We performed BrU-Seq after shRNA mediated depletion of Lsd1 in primary cultures of mouse cortical neurons.

ORGANISM(S): Mus musculus

PROVIDER: GSE93938 | GEO | 2020/09/01

REPOSITORIES: GEO

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LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers [RNA-Seq]

Project description:We performed sequencing of Nuclear RNA from Lsd1-WT, Lsd1-GT, KDM5c-WT, and KDM5C-KO mouse embryonic stem cells (mES). We also performed sequencing of Total RNA from Lsd1-WT and Lsd1-GT mES.

2020-09-01 | GSE94556 | GEO

LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers [ChIP-Seq]

Project description:We performed ChIP-Seq in Lsd1-WT, Lsd1-GT and Kdm5c-WT mouse embryonic stem cells (mES).

2020-09-01 | GSE94552 | GEO

LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers [GRO-Seq]

Project description:We performed GRO-Seq in Lsd1-WT and Lsd1-GT mouse embryonic stem cells (mES).SMCX_WT (KDM5c_WT) and SMCX_KO (KDM5c_KO) represent two additional mES cell lines used in the GRO-Seq study.

2020-09-01 | GSE93951 | GEO

KDM1A maintains genome-wide homeostasis of transcriptional enhancers.

Project description:Transcriptional enhancers enable exquisite spatiotemporal control of gene expression in metazoans. Enrichment of monomethylation of histone H3 lysine 4 (H3K4me1) is a major chromatin signature of transcriptional enhancers. Lysine (K)-specific demethylase 1A (KDM1A, also known as LSD1), an H3K4me2/me1 demethylase, inactivates stem-cell enhancers during the differentiation of mouse embryonic stem cells (mESCs). However, its role in undifferentiated mESCs remains obscure. Here, we show that KDM1A actively maintains the optimal enhancer status in both undifferentiated and lineage-committed cells. KDM1A occupies a majority of enhancers in undifferentiated mESCs. KDM1A levels at enhancers exhibit clear positive correlations with its substrate H3K4me2, H3K27ac, and transcription at enhancers. In Kdm1a-deficient mESCs, a large fraction of these enhancers gains additional H3K4 methylation, which is accompanied by increases in H3K27 acetylation and increased expression of both enhancer RNAs (eRNAs) and target genes. In postmitotic neurons, loss of KDM1A leads to premature activation of neuronal activity-dependent enhancers and genes. Taken together, these results suggest that KDM1A is a versatile regulator of enhancers and acts as a rheostat to maintain optimal enhancer activity by counterbalancing H3K4 methylation at enhancers.

| S-EPMC7849409 | biostudies-literature

LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers

Project description:LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers

| PRJNA362885 | ENA

LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-09-01 | GSE93952 | GEO

The LSD1/KDM1A neuro-specific isoform regulates neuronal differentiation through H3K9 demethylation [Affymetrix]

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

GR and LSD1/KDM1A-Targeted Gene Activation Requires Selective H3K4me2 Demethylation at Enhancers.

Project description:KDM1A-mediated H3K4 demethylation is a well-established mechanism underlying transcriptional gene repression, but its role in gene activation is less clear. Here, we report a critical function and mechanism of action of KDM1A in glucocorticoid receptor (GR)-mediated gene transcription. Biochemical purification of the nuclear GR complex revealed KDM1A as an integral component. In cell-free assays, GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting the loss of H3K4me1. Similarly, in cells, KDM1A binds to most GR binding sites in the genome, where it removes preprogrammed H3K4me2 but leaves H3K4me1 untouched. Blocking KDM1A catalytic activity prevents H3K4me2 removal, severely impairs GR binding to chromatin, and dysregulates GR-targeted genes. Taken together, these data suggest KDM1A-mediated H3K4me2 demethylation at GRBSs promotes GR binding and plays an important role in glucocorticoid-induced gene transcription, broadening the mechanisms that contribute to nuclear receptor-mediated gene activation.

| S-EPMC7433711 | biostudies-literature

Targeting the scaffolding role of LSD1 (KDM1A) poises acute myeloid leukemia cells for Retinoic Acid induced differentiation

Project description:The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells through degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knock-out, but LSD1 inhibition sensitizes them to physiological doses of RA without altering the stability of PML-RAR, and extends survival of leukemic mice upon RA treatment. Non-enzymatic activities of LSD1 are essential to block differentiation of leukemic cells, while the combination of LSD1 inhibitors (or LSD1 knock-out) with low doses of RA releases a differentiation-associated gene expression program, not strictly dependent on changes in histone H3K4 methylation (known substrate of LSD1). An integrated proteomic/epigenomic/mutational analysis showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin through inhibition of the interaction between LSD1 and GFI1, a relevant transcription factor in hematopoiesis.

2020-05-26 | PXD012954 | Pride

Integrative Analysis Reveals Histone Demethylase LSD1/KDM1A Regulates RNA Polymerase II Pausing

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

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