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The RNA binding protein LIN28A mediates chromatin dynamics during neuronal differentiation.

Title: The RNA binding protein LIN28A mediates chromatin dynamics during neuronal differentiation.
Authors: Piscitelli S; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; Cascone E; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; D'Ambrosio C; Proteomics and Mass Spectrometry Laboratory, ISPAAM, Italian National Research Council, Portici, Italy.; Divisato G; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; Giannino E; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; De Lisio L; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; Leoni G; Data science and Automation Department, IRBM, Pomezia, Italy.; D'Andrea D; School of Engineering Mathematics and Technology, University of Bristol, Bristol, UK.; Matassa DS; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; Lanzuolo C; INGM, Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy.; ITB-CNR, Institute of Biomedical Technologies, National Research Council, Segrate, Italy.; Rosti V; INGM, Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy.; ITB-CNR, Institute of Biomedical Technologies, National Research Council, Segrate, Italy.; Zizolfi MC; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; Matuozzo M; Proteomics and Mass Spectrometry Laboratory, ISPAAM, Italian National Research Council, Portici, Italy.; di Patrizio Soldateschi E; INGM, Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy.; ITB-CNR, Institute of Biomedical Technologies, National Research Council, Segrate, Italy.; Maiuri P; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; Scaloni A; Proteomics and Mass Spectrometry Laboratory, ISPAAM, Italian National Research Council, Portici, Italy.; Passaro F; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.; Parisi S; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. silvia.parisi@unina.it.
Source: Cell death and differentiation [Cell Death Differ] 2026 May 05. Date of Electronic Publication: 2026 May 05.
Publication Model: Ahead of Print
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9437445 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5403 (Electronic) Linking ISSN: 13509047 NLM ISO Abbreviation: Cell Death Differ Subsets: MEDLINE
Imprint Name(s): Publication: : London : Nature Publishing Group; Original Publication: London : Edward Arnold, c1994-
Abstract: The transition of embryonic stem cells (ESCs) from a pluripotent state to lineage commitment is governed by complex regulatory mechanisms, including chromatin remodeling, as well as transcriptional and post-transcriptional processes. Recent studies have emphasized the interplay between these mechanisms, revealing intricate, multilayered regulatory networks that require further elucidation. In this study, we reveal a new connection between the RNA-binding protein LIN28A and the epigenetic regulation of ESC differentiation. LIN28A is upregulated during the early stages of neural commitment and undergoes a shift in subcellular localization from the nucleus to the cytoplasm upon differentiation. Generation and analysis of Lin28a knockout (KO) ESCs revealed that, although these cells can self-renew, they exhibit a pronounced defect in differentiating into neural precursors. However, mesodermal and endodermal differentiation proceeds normally in Lin28a KO cells, suggesting a neuronal-specific function for LIN28A. Proteomic analyses revealed a dynamic, context-dependent LIN28A interactome, with distinct sets of putative interacting partners in ESCs compared to those in differentiating cells. Among the ESC-specific putative interactors, we validated an RNA-dependent association of LIN28A with components of Polycomb Repressive Complex 2 (PRC2), a key chromatin-modifying complex that deposits the repressive histone modification H3K27me3. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that loss of LIN28A results in persistent PRC2 occupancy at the promoters of developmental genes, accompanied by partial uncoupling between PRC2 binding and H3K27me3 deposition. Lin28a KO causes differentiation defects that are not rescued by pharmacological inhibition of PRC2 enzymatic activity, suggesting that LIN28A regulates PRC2 chromatin dynamics independently of H3K27me3 deposition. Furthermore, we identified an interaction between LIN28A and the long non-coding RNA Neat1, which may serve as a scaffold facilitating PRC2 eviction from chromatin. Taken together, our findings reveal a previously unrecognized role for LIN28A in regulating PRC2-mediated chromatin dynamics and underscore its importance in epigenetic control of neuronal differentiation.; (© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests
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Grant Information: P2022KBAT7 Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research); 2022P7R5CJ Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research); #2022-4RFLLA Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research); #P2022F3YRF Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research); 24306 AFM-Téléthon (French Muscular Dystrophy Association); #24976 Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
Entry Date(s): Date Created: 20260505 Latest Revision: 20260505
Update Code: 20260506
DOI: 10.1038/s41418-026-01753-2
PMID: 42086780
Database: MEDLINE

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