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Mechanistic and Epigenetic Partitioning of Lamina-Associated Chromatin Revealed by a Genome-Wide Imaging Screen

GSE303855 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing; Expression profiling by high throughput sequencing 45 samples Submitted 2025/08/27 Platform GPL30882Platform GPL18573Platform GPL24676Platform GPL34284
Summary
The nuclear periphery is a key site for heterochromatin organization in eukaryotic cells, where lamina-associated domains (LADs) promote transcriptional repression and genome stability. Despite their importance, the mechanisms governing LAD positioning in human cells remain poorly understood. To this end, we performed a genome-wide imaging-based screen and identified 101 genes critical for perinuclear LAD localization, with a significant enrichment for RNA-binding proteins. Among these, hnRNPK emerged as a key regulator, required for the perinuclear positioning of approximately 70% of LADs genome-wide. Loss of hnRNPK led to their repositioning away from the nuclear periphery without altering global heterochromatin state, yet resulted in misexpression of genes within these domains. Notably, hnRNPK-sensitive LADs are uniquely enriched for H3K27me3, distinguishing them from hnRNPK-insensitive LADs that are predominantly marked by H3K9me3. These findings reveal mechanistically distinct classes of LADs and suggest that specialized pathways underlie their spatial organization. Our results uncover a pivotal role for hnRNPK in regulating chromatin architecture and highlight the broader diversity of LAD tethering mechanisms.
Published in
Mechanistic and Epigenetic Partitioning of Lamina-Associated Chromatin Revealed by a Genome-Wide Imaging Screen
Walsh PJ, Kraeutler EB, Linares-Saldana R et al. · bioRxiv : the preprint server for biology 2025 · PMID 40832213 · doi:10.1101/2025.08.13.670143
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Direct links to NCBI, no account and no request form: the whole study as GSE303855_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 45 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1297768 and SRA study SRP604067. Searching any of these in the dataset finder brings you back here.

Study design
37 conditions, each sampled once — no replicated groups
RNA, siControl, ×4

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