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LSD1/KDM1A Maintains Genome-wide Homeostasis of Transcriptional Enhancers

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE93952 | GEO | 2020/09/01

REPOSITORIES: GEO

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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 [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

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

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

2020-09-01 | GSE93938 | GEO

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

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

| PRJNA362885 | ENA

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

The histone demethylase LSD1/KDM1A promotes the DNA damage response.

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

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

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

2015-06-05 | GSE63153 | GEO

LSD1/KDM1A inhibitors in clinical trials: advances and prospects.

Project description:Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.

| S-EPMC6894138 | biostudies-literature

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