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Lewis, R.* ; Sinigiani, V.* ; Maziak, N.* ; Koos, K.* ; Bersaglieri, C.* ; Zemp, I.* ; Ashiono, C.* ; Ciaudo, C.* ; Horvath, P. ; Vaquerizas, J.M.* ; Santoro, R.* ; Sharma, P.* ; Kutay, U.*

LBR and LAP2 mediate heterochromatin tethering to the nuclear periphery to preserve genome homeostasis.

Nat. Cell Biol. 28, 536-552 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
In most eukaryotic cells, euchromatin is localized in the nuclear interior, whereas heterochromatin is enriched at the nuclear envelope (NE). This conventional chromatin organization is established by heterochromatin tethering to the NE; however, its importance for cellular homeostasis is largely unexplored. One tether is constituted by the lamin B receptor (LBR) in mammals, but the enigmatic nature of other redundant tethers has hampered functional analyses. Here we demonstrate that downregulation of abundant, ubiquitous NE proteins can induce the global detachment of heterochromatin from the NE and its repositioning to the nuclear interior. We identify LBR and lamina-associated polypeptide 2 (LAP2) as key factors for peripheral heterochromatin positioning in differentiated and pluripotent mammalian cells. Their long-term loss leads to changes in three-dimensional chromatin organization and a reduction in repressive epigenetic marks, especially H3K27me3. These changes are associated with massive deregulation of gene expression, activation of antiviral innate immunity, and defects in cell fate determination.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Heterochromatin ; Euchromatin ; Heterochromatin Protein 1 ; Chromatin ; Lamin ; Tethering ; Epigenetics; Lamin B-receptor; Transposable Elements; Envelope Protein; Histone H4; Chromatin; Reveals; Dna; Organization; Chromosomes; Expression
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Journal Nature Cell Biology
Quellenangaben Volume: 28, Issue: 3, Pages: 536-552 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Reviewing status Peer reviewed
Institute(s) Institute of AI for Health (AIH)
Grants EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
Schweizerischer Nationalfonds zur Frderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
Academy of Medical Sciences and the Department of Business, Energy and Industrial Strategy (APR3\1017)
Lendlet BIOMAG 2018-342, H2020-Fair-CHARM, CZI Deep Visual Proteomics, HAS-NAP3, the ELKH-Excellence grant from OTKA-SNN
RCUK | Medical Research Council (MRC)