{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:14:00Z","timestamp":1788344040426,"version":"build-2803163510"},"posted":{"date-parts":[[2024,2,1]]},"group-title":"Neuroscience","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T00:00:00Z","timestamp":1706745600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["DC015000"],"award-info":[{"award-number":["DC015000"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DC022483"],"award-info":[{"award-number":["DC022483"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Spiral ganglion neurons (SGNs) are the primary afferent neurons that convey auditory information from the cochlea to the central nervous system. Pathogenic variants of human chromodomain helicase DNA-binding protein 4 (CHD4) cause Sifrim-Hitz-Weiss (SIHIWES) syndrome, a neurodevelopmental disorder associated with hearing loss. Here, we identified expression of CHD4, an ATP-dependent chromatin remodeler, in developing SGNs and proceeded to delete\n                  <jats:italic>Chd4<\/jats:italic>\n                  in mice. Auditory brainstem recordings showed that animals lacking Chd4 in SGNs exhibit hearing loss. SGNs are classified as type I and type II neurons, which display distinct peripheral innervation patterns. Notably, loss of CHD4 resulted in abnormal fasciculation of type I neurons and improper pathfinding of type II fibers. To uncover the underlying molecular mechanisms, we mapped genome-wide CHD4 chromatin occupancy in immortalized multipotent otic progenitor (iMOP)-derived neurons. Gene ontology analysis of CHD4 target genes revealed pathways governing axon guidance, axonal fasciculation, and ephrin receptor signaling.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , we observed upregulation of specific Eph\/ephrin genes in SGNs from\n                  <jats:italic>Chd4<\/jats:italic>\n                  -conditional knockout cochleae. Together, these results demonstrate that CHD4 modulates chromatin at cis-regulatory elements to repress a subset of axon guidance molecules during development. The coordinated regulation of multiple guidance cues is essential for establishing precise neural circuitry in the cochlea. Our findings reveal a critical role for CHD4-dependent epigenetic regulation in neural circuit wiring and offer a translational framework for strategies to regenerate SGNs.\n                <\/jats:p>","DOI":"10.1101\/2024.01.31.578202","type":"posted-content","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T19:30:11Z","timestamp":1706815811000},"source":"Crossref","is-referenced-by-count":1,"title":["Chromatin remodeling protein CHD4 regulates axon guidance of spiral ganglion neurons in the developing cochlea"],"prefix":"10.64898","author":[{"given":"Jihyun","family":"Kim","sequence":"first","affiliation":[{"name":"DLS Center for Collaborative Neuroscience and Stem Cell Research Center, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Martinez","sequence":"additional","affiliation":[{"name":"DLS Center for Collaborative Neuroscience and Stem Cell Research Center, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyun","family":"Qiu","sequence":"additional","affiliation":[{"name":"DLS Center for Collaborative Neuroscience and Stem Cell Research Center, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Laureano","sequence":"additional","affiliation":[{"name":"DLS Center for Collaborative Neuroscience and Stem Cell Research Center, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Hinman","sequence":"additional","affiliation":[{"name":"DLS Center for Collaborative Neuroscience and Stem Cell Research Center, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie Zhouli","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8617-5543","authenticated-orcid":false,"given":"Kelvin Y.","family":"Kwan","sequence":"additional","affiliation":[{"name":"DLS Center for Collaborative Neuroscience and Stem Cell Research Center, Rutgers University, Piscataway, NJ 08854, USA"},{"name":"Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026090202201547000_2024.01.31.578202v3.1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10244"},{"key":"2026090202201547000_2024.01.31.578202v3.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2011.01.004"},{"key":"2026090202201547000_2024.01.31.578202v3.3","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv416"},{"key":"2026090202201547000_2024.01.31.578202v3.4","doi-asserted-by":"publisher","DOI":"10.1016\/0378-5955(88)90061-5"},{"key":"2026090202201547000_2024.01.31.578202v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.06.003"},{"key":"2026090202201547000_2024.01.31.578202v3.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-5748(96)00120-7"},{"key":"2026090202201547000_2024.01.31.578202v3.7","doi-asserted-by":"crossref","first-page":"102414","DOI":"10.1016\/j.mex.2023.102414","article-title":"Auditory brainstem response (ABR) waveform analysis program","volume":"11","year":"2023","journal-title":"MethodsX"},{"key":"2026090202201547000_2024.01.31.578202v3.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2011.01.016"},{"key":"2026090202201547000_2024.01.31.578202v3.9","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.26"},{"key":"2026090202201547000_2024.01.31.578202v3.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2013.04.003"},{"key":"2026090202201547000_2024.01.31.578202v3.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.10.029"},{"key":"2026090202201547000_2024.01.31.578202v3.12","doi-asserted-by":"crossref","unstructured":"Coate, T. 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