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| Status |
Public on Dec 04, 2023 |
| Title |
Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Other
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| Summary |
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.
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| 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.
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| Web link |
https://doi.org/10.1038/s41467-024-45773-3
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| Contributor(s) |
Niñerola S, del Blanco B, Barco A |
| Citation(s) |
38453932 |
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| Submission date |
Jun 29, 2023 |
| Last update date |
Mar 08, 2024 |
| Contact name |
Sergio Niñerola |
| E-mail(s) |
sninerola@umh.es
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| Phone |
+34646912958
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| Organization name |
CSIC-Instituto de Neurociencias de Alicante
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| Department |
Molecular Neurobiology and Neuropathology
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| Lab |
Transcriptional and epigenetic mechanisms of neuronal plasticity
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| Street address |
Avenida Santiago Ramon y Cajal, s/n
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| City |
San Juan de Alicante |
| State/province |
Alicante |
| ZIP/Postal code |
03550 |
| Country |
Spain |
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| Platforms (3) |
| GPL16417 |
Illumina MiSeq (Mus musculus) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (37)
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| GSM7519412 |
RNA_Kdm1a_ifKO, rep1 |
| GSM7519413 |
RNA_Kdm1a_ifKO, rep2 |
| GSM7519414 |
RNA_Kdm1a_ifKO, rep3 |
| GSM7519415 |
ChIP_H3k4me3_WT, rep1 |
| GSM7519416 |
ChIP_H3k4me3_WT, rep2 |
| GSM7519417 |
ChIP_H3k4me3_ifKO, rep1 |
| GSM7519418 |
ChIP_H3k4me3_ifKO, rep2 |
| GSM7519419 |
ChIP_H3k4me3_ifKO, rep3 |
| GSM7519420 |
ChIP_H3k4me1_WT, rep1 |
| GSM7519421 |
ChIP_H3k4me1_WT, rep2 |
| GSM7519422 |
ChIP_H3k4me1_WT, rep3 |
| GSM7519423 |
ChIP_H3k4me1_ifKO, rep1 |
| GSM7519424 |
ChIP_H3k4me1_ifKO, rep2 |
| GSM7519425 |
ChIP_H3k4me1_ifKO, rep3 |
| GSM7519426 |
ChIP_H3k27me3_WT, rep1 |
| GSM7519427 |
ChIP_H3k27me3_WT, rep2 |
| GSM7519428 |
ChIP_H3k27me3_ifKO, rep1 |
| GSM7519429 |
ChIP_H3k27me3_ifKO, rep2 |
| GSM7519430 |
ChIP_H3k27ac_WT, rep1 |
| GSM7519431 |
ChIP_H3k27ac_WT, rep2 |
| GSM7519432 |
ChIP_H3k27ac_WT, rep3 |
| GSM7519433 |
ChIP_H3k27ac_ifKO, rep1 |
| GSM7519434 |
ChIP_H3k27ac_ifKO, rep2 |
| GSM7519435 |
ChIP_H3k27ac_ifKO, rep3 |
| GSM7519436 |
ChIA-PET, CTCF |
| GSM7519437 |
4C_WT,rep1 |
| GSM7519438 |
4C_WT,rep2 |
| GSM7519439 |
4C_ifKO,rep3 |
| GSM7519440 |
4C_WT,rep4 |
| GSM7519441 |
4C_WT,rep5 |
| GSM7519442 |
4C_ifKO,rep2 |
| GSM7519443 |
4C_ifKO,rep4 |
| GSM7519444 |
ChIP_KDM1a |
| GSM7519445 |
ChIP_KDM1a_2 |
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| Relations |
| BioProject |
PRJNA989189 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE236182_KDM1a_allmerged_hippocampus.bam.RPGC.bw |
341.4 Mb |
(ftp)(http) |
BW |
| GSE236182_KDM1a_merge.bam.RPKM.bw |
59.8 Mb |
(ftp)(http) |
BW |
| GSE236182_KDM1a_wt_merge.bam.RPKM.bw |
62.2 Mb |
(ftp)(http) |
BW |
| GSE236182_RAW.tar |
1.9 Gb |
(http)(custom) |
TAR (of BEDGRAPH, BEDPE, BIGWIG, HIC, WIG) |
| GSE236182_S1K_merged_mapq30.bam.bw |
511.6 Mb |
(ftp)(http) |
BW |
| GSE236182_S1W_merged_mapq30.bam.bw |
386.8 Mb |
(ftp)(http) |
BW |
| GSE236182_S3K_merged.mapq30.bam.SCALESIZEFACTORS.bw |
384.0 Mb |
(ftp)(http) |
BW |
| GSE236182_S3W_merged.mapq30.bam.SCALESIZEFACTORS.bw |
308.2 Mb |
(ftp)(http) |
BW |
| GSE236182_WTLSD1_H3K27ac.mapq30.bam.RPGC.bw |
536.6 Mb |
(ftp)(http) |
BW |
| GSE236182_WTLSD1_H3K27me3.mapq30.bam.SCALESIZEFACTORS.bw |
444.6 Mb |
(ftp)(http) |
BW |
| GSE236182_ifKOLSD1_H3K27ac.mapq30.bam.RPGC.bw |
539.3 Mb |
(ftp)(http) |
BW |
| GSE236182_ifKOLSD1_H3K27me3.mapq30.bam.SCALESIZEFACTORS.bw |
439.4 Mb |
(ftp)(http) |
BW |
| GSE236182_raw_counts.txt.gz |
371.8 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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