Kim Jihyun, Martinez Edward, Qiu Jingyun, Zhouli Ni Julie, Kwan Kelvin Y
Keck Center for Collaborative Neuroscience and Stem Cell Research Center, Rutgers University, Piscataway, NJ 08854, USA.
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
bioRxiv. 2024 Feb 1:2024.01.31.578202. doi: 10.1101/2024.01.31.578202.
The chromodomain helicase binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler. pathogenic variants of cause Sifrim-Hitz-Weiss syndrome (SIHIWES). Patients with SIHIWES show delayed development, intellectual disability, facial dysmorphism, and hearing loss. Many cochlear cell types, including spiral ganglion neurons (SGNs), express CHD4. SGNs are the primary afferent neurons that convey sound information from the cochlea, but the function of CHD4 in SGNs is unknown. We employed the Neurog1(Ngn1) CreERT conditional knockout animals to delete in SGNs. SGNs are classified as type I and type II neurons. SGNs lacking CHD4 showed abnormal fasciculation of type I neurons along with improper pathfinding of type II fibers. CHD4 binding to chromatin from immortalized multipotent otic progenitor-derived neurons was used to identify candidate target genes in SGNs. Gene ontology analysis of CHD4 target genes revealed cellular processes involved in axon guidance, axonal fasciculation, and ephrin receptor signaling pathway. We validated increased transcripts in SGNs from conditional knockout cochleae. The results suggest that CHD4 attenuates the transcription of axon guidance genes to form the stereotypic pattern of SGN peripheral projections. The results implicate epigenetic changes in circuit wiring by modulating axon guidance molecule expression and provide insights into neurodevelopmental diseases.
染色质结构域解旋酶结合蛋白4（CHD4）是一种依赖ATP的染色质重塑因子。其致病性变异会导致西夫林 - 希茨 - 魏斯综合征（SIHIWES）。患有SIHIWES的患者表现出发育迟缓、智力残疾、面部畸形和听力丧失。许多耳蜗细胞类型，包括螺旋神经节神经元（SGN），都表达CHD4。SGN是将声音信息从耳蜗传递的主要传入神经元，但CHD4在SGN中的功能尚不清楚。我们利用Neurog1（Ngn1）CreERT条件性敲除动物来删除SGN中的CHD4。SGN分为I型和II型神经元。缺乏CHD4的SGN表现出I型神经元的异常成束以及II型纤维的路径寻找不当。利用CHD4与永生化多能耳祖细胞衍生神经元的染色质结合来鉴定SGN中的候选靶基因。CHD4靶基因的基因本体分析揭示了与轴突导向、轴突成束和 Ephrin 受体信号通路相关的细胞过程。我们验证了条件性敲除耳蜗的SGN中某些转录本的增加。结果表明，CHD4减弱轴突导向基因的转录，以形成SGN外周投射的刻板模式。这些结果表明通过调节轴突导向分子表达在神经回路布线中存在表观遗传变化，并为神经发育疾病提供了见解。
