---
title: "NSD2 loss in cochlear hair cells alters H3K36me2, increases ECM genes and impairs hearing"
id: "biorxiv-10-nsd2-deficiency-disrupts-the-epigenetic-landscape-of-cochlear-hair-cells-to"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-10-nsd2-deficiency-disrupts-the-epigenetic-landscape-of-cochlear-hair-cells-to"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.21.753379v1?rss=1"
published_at: "2026-09-23T09:50:14.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# NSD2 loss in cochlear hair cells alters H3K36me2, increases ECM genes and impairs hearing
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-10-nsd2-deficiency-disrupts-the-epigenetic-landscape-of-cochlear-hair-cells-to
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.21.753379v1?rss=1)
- **Published At:** 2026-09-23T09:50:14.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study used a cochlear hair cell (HC)-specific Nsd2 knockout mouse to test NSD2 function in HC maturation and hearing. - Loss of NSD2 produced severe structural defects in stereociliary bundles and caused profound hearing impairment in the model. - Multi-omics profiling showed NSD2 deficiency reduces levels of **H3K36me2** and changes genome-wide chromatin accessibility and gene expression. - Reduced H3K36me2 was associated with transcriptional upregulation of **extracellular matrix (ECM)** genes, leading to excessive collagen accumulation and disrupted tissue architecture in the cochlea. - The authors report that targeted **ECM intervention** partially ameliorated hearing damage caused by NSD2 deficiency, supporting a causal role for ECM accumulation in the phenotype. - The work proposes an epigenetic mechanism in which **NSD2** regulates HC maturation by restraining chromatin remodeling–driven ECM overexpression. - The study suggests a potential therapeutic direction for hearing impairment via modulation of ECM accumulation; specific therapeutic agents and clinical translation details were not reported in the source. - This article is a preprint and has not undergone peer review; funding was provided by the National Natural Science Foundation of China (U23A20441).
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Ziyi Wang 1 Shanghai Jiao Tong University; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ziyi%2BWang%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Wang%20Z&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AZiyi%2BWang%2B) * [ORCID record for Ziyi Wang](http://orcid.org/0009-0002-9262-2968 "Open in new tab") Yue Xu 2 Shanghai Jiaotong University Press; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Yue%2BXu%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Xu%20Y&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AYue%2BXu%2B) Xiaojie Ma 3 Department of Otolaryngology, Qilu Hospital, Shandong University; 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However, whether and how NSD2, a histone H3 lysine 36 (H3K36) dimethyltransferase, affects cochlear HC maturation remains unclear. Here, we established an HC-specific Nsd2 knockout mouse model and discovered that the loss of NSD2 results in severe structural defects in stereociliary bundles and profound hearing impairment. Integrated multi-omics profiling revealed that NSD2 deficiency leads to a decreased expression of H3K36me2, which in turn alters genome-wide chromatin accessibility and gene expression. Mechanistically, NSD2 deficiency triggers the aberrant upregulation of extracellular matrix (ECM) genes at the transcriptional level, causing excessive collagen accumulation and compromising tissue structure. Crucially, ECM intervention can mitigate NSD2-deficiency mediated hearing damage. Our study reveals an epigenetic mechanism by which NSD2 regulates cochlear HC maturation through inhibition of chromatin remodeling-induced ECM accumulation, and provides a potential new therapeutic direction for hearing impairment. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared National Natural Science Foundation of China, U23A20441 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. [Donate to openRxiv ](https://www.zeffy.com/en-US/donation-form/donate-to-make-a-difference-10981) [ Back to top](https://www.biorxiv.org/content/10.64898/2026.09.21.753379v1?rss=1#page) [ Previous](https://www.biorxiv.org/content/10.64898/2026.09.21.753347v1 "Living with the invader: two native deer, two outcomes along a gradient of axis deer invasion") Posted September 23, 2026. 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