Unliganded thyroid hormone receptor regulates NPC homeostasis via NuRD-mediated H3K9ac modulation

Mutations in thyroid hormone receptor (TR) are etiologically linked to severe neurodevelopmental disorders, highlighting its critical role in the development and function of the nervous system. However, since neural progenitor cell (NPC) emergence precedes endogenous thyroid hormone synthesis, the ligand-independent functions of TR during early neurogenesis remain elusive. We employed hESC-derived NPCs in combination with TR knockdown to investigate the functions of unliganded TR (uTR). By integrating multi-omics approaches, including RNA sequencing, co-immunoprecipitation coupled with mass spectrometry, ChIP-seq profiling of NuRD components and histone modifications, and high-throughput chromatin conformation capture techniques, we elucidated the mechanisms by which uTR regulates neurogenesis and differentiation. Depletion of uTR triggered extensive transcriptional reprogramming, significantly disrupting key neurodevelopmental pathways. Mechanistically, we demonstrate that uTR physically interacts with the Nucleosome Remodeling and Deacetylase (NuRD) complex. Notably, TR knockdown predominantly compromised the protein stability and genomic recruitment of the NuRD subunit MTA1. The loss of uTR was accompanied by altered NuRD-mediated repression and a marked increase in histone H3 lysine 9 acetylation (H3K9ac), while H3K27ac profiles and the higher-order 3D chromatin architecture were largely maintained. Our findings collectively establish uTR as a critical epigenetic modulator that fine-tunes the neurodevelopmental program, potentially through the uTR-NuRD-H3K9ac signaling axis during the key early window of neurogenesis. This study highlights the importance of ligand-independent signaling in maintaining chromatin homeostasis during early neural development and provides novel insights into the pathogenesis of TR-related disorders.