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Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons

ABSTRACT: Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons

PROVIDER: PRJNA989189 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25080000.fastq.gz	Fastqsanger.gz
	SRR25080001.fastq.gz	Fastqsanger.gz
	SRR25080002.fastq.gz	Fastqsanger.gz
	SRR25080003.fastq.gz	Fastqsanger.gz
	SRR25080004.fastq.gz	Fastqsanger.gz

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Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons

Project description: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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Long-distance association of topological boundaries through nuclear condensates (Hi-C)

Project description:Chromatin is partitioned into distinct topological domains in an activity-dependent manner, with topological boundaries limiting the interaction between adjacent domains. Recent studies support the concept that several well-established nuclear compartments are assembled as ribonucleoprotein condensates. Here we ask whether the physical processes driving the assembly of the nuclear condensates play any role in three-dimensional chromatin architecture. We report that the insulation of approximately 20% of topological boundaries in human embryonic stem cells is substantially weakened following brief treatment with 1,6-hexanediol, a chemical known to disrupt several nuclear condensates. The disrupted boundaries are characterized by a high level of transcription, striking spatial clustering, and the augmented presence of transcription units widely expressed in diverse cell types. These topological boundary regions tend to be spatially associated, even inter-chromosomally, and segregate with nuclear speckles. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring widely-expressed transcription units and associated transcriptional condensates.

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Project description:Long-distance association of topological boundaries through nuclear condensates

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Long-distance association of topological boundaries through nuclear condensates (ChIP-Seq)

Project description:Long-distance association of topological boundaries through nuclear condensates (ChIP-Seq)