Unliganded Thyroid Hormone Receptor Steers Early Neural Development Without Its Hormone

Thyroid hormone receptor mutations are etiologically linked to severe neurodevelopmental disorders, underscoring the receptor’s critical role in nervous system development and function. Yet a puzzle has persisted: neural progenitor cells emerge before endogenous thyroid hormone synthesis begins, meaning the receptor operates in a hormone-free state during the earliest stages of brain formation. A new study published in Cell & Bioscience addresses this gap by investigating the ligand-independent functions of unliganded thyroid hormone receptor during early neurogenesis, revealing that the receptor acts as an epigenetic modulator through a signaling axis involving the NuRD complex and histone H3 lysine 9 acetylation.

To dissect these mechanisms, the investigators integrated multiple genomic and proteomic approaches. RNA sequencing captured the transcriptional consequences of receptor depletion. Co-immunoprecipitation coupled with mass spectrometry identified physical interaction partners. ChIP-seq profiling mapped the genomic occupancy of Nucleosome Remodeling and Deacetylase complex components and key histone modifications. High-throughput chromatin conformation capture techniques assessed whether higher-order three-dimensional chromatin architecture changed when the receptor was removed.

The results show that depletion of unliganded thyroid hormone receptor triggered extensive transcriptional reprogramming, significantly disrupting key neurodevelopmental pathways.

Mechanistically, the study demonstrates that unliganded thyroid hormone receptor physically interacts with the Nucleosome Remodeling and Deacetylase complex, a chromatin-remodeling assembly known for its repressive effects on gene activity.

A particularly notable observation concerned the NuRD subunit MTA1. When thyroid hormone receptor was knocked down, the protein stability and genomic recruitment of MTA1 were predominantly compromised.

The consequences of losing unliganded receptor extended to histone modifications. The researchers found that the absence of the receptor was accompanied by altered NuRD-mediated repression and a marked increase in histone H3 lysine 9 acetylation, a mark generally associated with open, transcriptionally permissive chromatin. In contrast, H3K27ac profiles and the higher-order three-dimensional chromatin architecture were largely maintained.

Taken together, these findings establish unliganded thyroid hormone receptor 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. The study highlights the importance of ligand-independent signaling in maintaining chromatin homeostasis during early neural development and offers novel insights into the pathogenesis of TR-related disorders, which may arise not only from defective hormone responsiveness but also from disrupted chromatin regulation in progenitor cells that have never encountered thyroid hormone.

It should be noted that the findings derive from human embryonic stem cell-derived neural progenitor cells, an in vitro model of early neurogenesis, and the published version is a peer-reviewed, accepted manuscript shared early to provide faster access, subject to further edits before the final Version of Record.

Subject of Research: Ligand-independent epigenetic regulation of neural progenitor cells by unliganded thyroid hormone receptor

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

Article References: Sun, X., Lai, J., Li, L., Li, X., Cheng, Z., Liu, M., Li, Y., Wang, L., Huang, Z., Cao, C., & Li, F. (2026). Unliganded thyroid hormone receptor regulates NPC homeostasis via NuRD-mediated H3K9ac modulation. Cell & Bioscience. https://doi.org/10.1186/s13578-026-01673-1

Image Credits: AI Generated

DOI: 10.1186/s13578-026-01673-1

Keywords: thyroid hormone receptor, neural progenitor cells, NuRD complex, H3K9ac, epigenetics, neurogenesis, hESC-derived NPCs, MTA1, chromatin homeostasis, neurodevelopmental disorders, ChIP-seq, 3D chromatin architecture