Significance: This article presents a unique genome-wide transcriptome and cistrome analysis for thyroid hormone receptors. It defines 3,3′,5-triiodo- L -thyronine (T3) target genes in a neural cell line expressing either TRα1 or TRβ1. A substantial fraction of the T3 target genes display a marked preference for one of the two receptors. However, receptor-selective regulation of T3 target genes does not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRβ1 intrinsic properties contributes to the divergent evolution of the receptors’ function.

Molecular mechanisms underlying terminal differentiation of B cells into plasma cells are major determinants of adaptive immunity but remain only partially understood. Here we present the transcriptional and epigenomic landscapes of cell subsets arising from activation of human naive B cells and differentiation into plasmablasts. Cell proliferation of activated B cells was linked to a slight decrease in DNA methylation levels, but followed by a committal step in which an S phase-synchronized differentiation switch was associated with an extensive DNA demethylation and local acquisition of 5-hydroxymethylcytosine at enhancers and genes related to plasma cell identity. Downregulation of both TGF-?1/SMAD3 signaling and p53 pathway supported this final step, allowing the emergence of a CD23-negative subpopulation in transition from B cells to plasma cells. Remarkably, hydroxymethylation of PRDM1, a gene essential for plasma cell fate, was coupled to progression in S phase, revealing an intricate connection among cell cycle, DNA (hydroxy)methylation, and cell fate determination.

Thyroid hormone is necessary for normal development of the central nervous system, as shown by the severe mental retardation syndrome affecting hypothyroid patients with low levels of active thyroid hormone. The postnatal defects observed in hypothyroid mouse cerebellum are recapitulated in mice heterozygous for a dominant-negative mutation of Thra, the gene encoding the ubiquitous TRα1 receptor. Using CRE/loxP-mediated conditional expression approach, we found that this mutation primarily alters the differentiation of Purkinje cells and Bergmann glia, two cerebellum-specific cell types. These primary defects indirectly affect cerebellum development in a global manner. Notably, the inward migration and terminal differentiation of granule cell precursors is impaired. Therefore, despite the broad distribution of its receptors, thyroid hormone targets few cell types that exert a predominant role in the network of cellular interactions that govern normal cerebellum maturation.

Neurons in the CNS of higher vertebrates lose their ability to regenerate their axons at a stage of development that coincides with peak circulating thyroid hormone (T₃) levels. Here, we examined whether this peak in T₃is involved in the loss of axonal regenerative capacity in Purkinje cells (PCs). This event occurs at the end of the first postnatal week in mice. Using organotypic culture, we found that the loss of axon regenerative capacity was triggered prematurely by early exposure of mouse PCs to T₃, whereas it was delayed in the absence of T₃. Analysis of mutant mice showed that this effect was mainly mediated by the T₃receptor α1. Using gain- and loss-of-function approaches, we also showed that Krüppel-like factor 9 was a key mediator of this effect of T₃. These results indicate that the sudden physiological increase in T₃during development is involved in the onset of the loss of axon regenerative capacity in PCs. This loss of regenerative capacity might be part of the general program triggered by T₃throughout the body, which adapts the animal to its postnatal environment.

Thyroid hormone (T(3)) can trigger a massive differentiation of cultured oligodendrocytes precursor cells (OPC) by binding the nuclear T(3) receptor α1 (TRα1). Whether this reflects a physiological function of TRα1 remains uncertain. Using a recently generated mouse model, in which CRE/loxP recombination is used to block its function, we show that TRα1 acts at two levels for the in vivo differentiation of OPC in mouse cerebellum. At the early postnatal stage, it promotes the secretion of several neurotrophic factors by acting in Purkinje neurons and astrocytes, defining an environment suitable for OPC differentiation. At later stages, TRα1 acts in a cell-autonomous manner to ensure the complete arrest of OPC proliferation. These data explain contradictory observations made on various models and outline the importance of T(3) signaling both for synchronizing postnatal neurodevelopment and restraining OPC proliferation in adult brain.