U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

SRX20833419: GSM7519417: ChIP_H3k4me3_ifKO, rep1; Mus musculus; ChIP-Seq
2 ILLUMINA (Illumina HiSeq 2500) runs: 39.1M spots, 2G bases, 986.9Mb downloads

External Id: GSM7519417_r1
Submitted by: Transcriptional and epigenetic mechanisms of neuronal plasticity, Molecular Neurobiology and Neuropathology, CSIC-Instituto de Neurociencias de Alicante
Study: Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
show Abstracthide Abstract
Although Kdm1a is the most expressed histone demethylase in neurons, its molecular function in the adult brain remains unknown. Here, we found that inducible and forebrain-restricted knockout (ifKO) mice, in which Kdm1a is specifically eliminated in forebrain excitatory neurons during adulthood, display a prominent transcriptional and epigenomic dysregulation signature characterized by the neuronal expression of nonneuronal genes. The combination of super-resolution microscopy images and multi-omic analysis integrating transcriptome, epigenome and chromatin conformation data showed that these genes are target of the polycomb repressor complex 2 (PRC2) and locate in H3K27me3-microdomains encapsulated within the euchromatin compartment. Furthermore, functional assays revealed that both the catalytic activity and the N-terminus intrinsically disordered region of Kdm1a, which provides phase separation properties, are needed to maintain the boundaries between these silent micro-domains and the active chromatin environment. As a result, Kdm1a loss led to the spreading of active histone modifications into the PRC2-repressed genes causing their de-repression. Intriguingly, the investigation of aged mice suggested that these boundaries may also weaken during natural aging. Overall, these results underscore the role of Kdm1a safeguarding chromatin compartmentalization, nuclear phase separation and gene silencing in the adult and aging brain. Overall design: Expression profiling, Genome binding/occupancy profiling, and chromosome conformation capture by high throughput sequencing for WT and ifKO-Kdm1a mice. Chromatin interaction analysis with paired-end tag sequencing for CTCF in WT.
Sample: ChIP_H3k4me3_ifKO, rep1
SAMN36084911 • SRS18110764 • All experiments • All runs
Organism: Mus musculus
Library:
Name: GSM7519417
Instrument: Illumina HiSeq 2500
Strategy: ChIP-Seq
Source: GENOMIC
Selection: ChIP
Layout: SINGLE
Construction protocol: For RNA, total RNA was extracted from hippocampal tissue with TRI reagent (Sigma-Aldrich) as recommended by the manufacturer. Subsequently, genomic DNA was eliminated by a treatment with DNAse I (Qiagen) for 30 min at 25ºC. Followed by precipitation with phenol-chloroform-isoamyl alcohol (Sigma-Aldrich). ChIPs were performed as previously described in detail (Galvão-Ferreira et al., 2017) with minor modifications. Briefly, 3 μg of antibody were incubated with Dynabeads coated to Protein G (Invitrogen) in RIPA-150 buffer (50 mM Tris-HCl, 150 mM NaCl, 1 mM, EDTA, 0.1% SDS, 1% Triton X-100, and 0.1% sodium deoxycholate; pH 8) for 6-18 h at 4°C in agitation. Nuclei from hippocampal cells were extracted in a dounce homogenizer as explained for the FANS method. Samples were fixed with 1% formaldehyde (Sigma-Aldrich) for 10 min at room temperature followed by 0.1 M glycine for 5 min to stop the fixation. Nuclei were centrifuged at 1,5 G, and the pellet was resuspended in 100 μL of SDS lysis buffer (1% SDS, 10 mM EDTA, 50 mM Tris; pH 8) prior to its sonication in a Bioruptor Pico (Diagenode) for 12 cycles of 15 s on/30 s off. After 6 min of centrifugation at 13000 rpm, the supernatant containing isolated chromatin was collected. Samples were diluted in 900 μL of ChIP Dilution buffer (0.01% SDS, 1.1% Triton X-100, 1.2 mM EDTA, 16.7 mM Tris-HCl, 167 mM NaCl; pH 8) and incubated overnight at 4°C with the antibody-Dynabeads mix. Beads were thoroughly rinsed at 4ºC as follows: two washes in RIPA-150 buffer, three washes in RIPA-500 buffer (50mM Tris-HCl, 500 mM NaCl, 1 mM, EDTA, 0.1% SDS, 1% Triton X-100, 0.1% sodium deoxycholate; pH 8), two washes in RIPA LiCl buffer (50 mM Tris-HCl, 1 mM EDTA, 1% NP-40, 0.7%, sodium deosycholate, 500 mM LiCl2), and two final washes in TE buffer (10 mM Tris-HCl, pH 8.0, 1 mM EDTA; pH 8.0), five minutes each. Samples were resuspended in 200 μl Elution buffer (10 mM Tris-HCl, 5 mM EDTA, 300 mM NaCl, 0.5% SDS; pH 8) and treated with 1 μl of 10 mg/mL RNase A (Fermentas) overnight at 65°C in agitation for crosslink reversion. Samples were treated with 3 μl of 20 mg/mL Proteinase K (Thermo Scientific) for 2 hours at 55°C in agitation. Last, DNA precipitation was performed by phenol-chloroform-isoamyl alcohol (Sigma-Aldrich). For Kdm1a ChIP, some modification were applied as in (Lipinski et al., 2020). In brief, samples required a stronger fixation treatment in 1% PFA for 30 min at 37ºC. To fragment these highly fixed samples, 43 cycles of sonication (30 s On, 30 s Off) were applied in a Bioruptor Pico (Diagenode). SDS lysis buffer was modified to RIPA buffer (0.1% SDS, 1% IGEPAL, and 0.5% sodium deoxycholate). Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) using a CTCF-specific antibody (Abclonal Cat # ab70303) was performed as described in the in situ ChIA-PET protocol (Wang et al., 2021) on approximately 10 million nuclei of hippocampal excitatory neurons sorted by FANS as described above. 4C-seq, was performed as previously described (Krijger et al., 2020) with minimal changes. Approximately 5 million hippocampal nuclei were fixed at 1 % with PFA. The restriction enzyme cutting order was Dpn II as the primary enzyme and Csp6I as the secondary enzyme. Ligated chromatin was phenol-chloroform extracted and ethanol precipitated. Reactions were then further purified with Ampure XP beads with a 0.8x ratio of bead solution to library following the manufactures instructions. Samples were then quantified with Qubit and 4C-seq libraries were sequenced using an Illumina high-throughput sequencing equip. For RNA three mice were used per genotype (Kdm1a-ifKO and their control littermates) and Poly-A libraries were generated. For RNA and ChIPseq, libraries were generated for each independent sample and single-end sequenced in a HiSeq 2500 apparatus from Illumina. For ChIAPet, librearies were generated and paired end and 150 pb were sequenced and emrged from Miseq, Nextseq 500/550 and Hiseq 3000/4000 aparatus. PolyA RNAseq, ChIP-seq, 4C-seq and ChIAPet
Runs: 2 runs, 39.1M spots, 2G bases, 986.9Mb
Run# of Spots# of BasesSizePublished
SRR2507999910,864,207543.2M268.7Mb2023-12-04
SRR2508000028,229,0891.4G718.2Mb2023-12-04

ID:
28264906

Supplemental Content

Search details

See more...

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...