FOXA1 Chromatin Binding is Regulated by LSD1-Mediated Demethylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA470707 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7140760.fastq.gz | Fastqsanger.gz | |||
| SRR7140770.fastq.gz | Fastqsanger.gz | |||
| SRR7140780.fastq.gz | Fastqsanger.gz | |||
| SRR7140790.fastq.gz | Fastqsanger.gz | |||
| SRR7140761.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Lineage-specific chromatin binding of FOXA1 is regulated by LSD1-mediated demethylation
| PRJNA627113 | ENA
Project description:We report that the winged helix transcription factor FOXA1 is unexpectedly associated with components of single and double stranded-DNA repair complexes. Biochemical studies and high-throughput approaches validated the hierarchical composition of this FOXA1-nucleated machinery and revealed the dependency on FOXA1 for global targeting of the key repair polymerase POLB. Genome-wide DNA methylomes at single-base resolution demonstrated that FOXA1-DNA repair complex is functionally linked to DNA demethylation in a lineage specific fashion. Loss-of-function studies indicate that a significant portion of FOXA1-bound regions display localized reestablishment of methylation and that the subsets with most consistent hypermethylation are represented by active promoters and enhancers that also exhibit the greatest depletion of POLB following FOXA1 removal. Consistently, forced expression of FOXA1 commits its binding sites to an active DNA demethylation in a POLB dependent manner. Finally, we showed that FOXA1-associated DNA demethylation is tightly coupled with genomic targeting of estrogen receptor and estrogen responsiveness. Together, our results link FOXA1-associated DNA demethylation to its transcriptional pioneering.
2016-06-08 | PXD004271 | Pride
Project description:Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates. Determine the role of LSD1 in androgen signaling.
2014-12-12 | E-GEOD-52201 | biostudies-arrayexpress
Project description:We report that the winged helix transcription factor FOXA1 is unexpectedly associated with components of single and double stranded-DNA repair complexes. Biochemical studies and high-throughput approaches validated the hierarchical composition of this FOXA1-nucleated machinery and revealed the dependency on FOXA1 for global targeting of the key repair polymerase POLB. Genome-wide DNA methylomes at single-base resolution demonstrated that FOXA1-DNA repair complex is functionally linked to DNA demethylation in a lineage specific fashion. Loss-of-function studies indicate that a significant portion of FOXA1-bound regions display localized reestablishment of methylation and that the subsets with most consistent hypermethylation are represented by active promoters and enhancers that also exhibit the greatest depletion of POLB following FOXA1 removal. Consistently, forced expression of FOXA1 commits its binding sites to an active DNA demethylation in a POLB dependent manner. Finally, we showed that FOXA1-associated DNA demethylation is tightly coupled with genomic targeting of estrogen receptor and estrogen responsiveness. Together, our results link FOXA1-associated DNA demethylation to its transcriptional pioneering.
2016-06-08 | GSE80808 | GEO
Project description:FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1-4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.
| S-EPMC7541538 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-09-29 | GSE114268 | GEO
Project description:Lysine Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4), but has coactivator function on some genes through unclear mechanisms. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and has a distinct AR-linked coactivator function mediated by demethylation of other substrates.
2014-12-12 | GSE52201 | GEO
Project description:We show in prostate cancer cells that LSD1 co-localizes with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding.
2020-07-14 | GSE148926 | 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: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