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A Nature Research Journal. A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor TR. In this model, the unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors to repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators to activate transcription. Here we show that in addition to hormone-independent TR occupancy, ChIP-seq against endogenous TR in mouse liver tissue demonstrates considerable hormone-induced TR recruitment to chromatin associated with chromatin remodelling and activated gene transcription.

Genome-wide footprinting analysis using DNase-seq provides little evidence for TR footprints both in the absence and presence of hormone, suggesting that unliganded TR engagement with repressive complexes on chromatin is, similar to activating receptor complexes, a highly dynamic process. This dynamic and ligand-dependent interaction with chromatin is likely shared by all steroid hormone receptors regardless of their capacity to repress transcription in the absence of ligand. Synthetic thyroid hormones are one of the most prescribed drugs worldwide to treat hypothyroidism.

Each subtype is expressed in a tissue-specific manner. TR shares many structural and functional similarities with other members of the receptor family. However, in contrast to receptors such progesterone receptor PR and glucocorticoid receptor GR , unliganded TR localizes primarily to the nucleus 2 and interacts with nucleosome-embedded DNA 3.

Binding of hormone is thought to induce a conformational change of TR, causing displacement of co-repressors and recruitment of co-activators 7 , 8 , 9 , This relatively simple bimodal switch, initially described in the late nineties, results in a transition from gene repression to gene activation Currently, this model is generally accepted for a basic understanding of TR-regulated gene transcription for recent reviews see, for example, refs 12 , 13 , 14 and also discussed as a general principle for nuclear receptors and other transcription factors TFs 15 , We have previously shown that genomic scale studies using a combination of DNase-seq and chromatin immunoprecipitation sequencing ChIP-Seq inform our understanding of steroid hormone receptors interaction with chromatin 17 , 18 , 19 , 20 ; however, such data is currently unavailable for endogenous TR.

We confirm that the unliganded TR indeed interacts with a number of regions in the genome. However, in contrast to the bimodal switch model, we find evidence for considerable ligand-dependent TR recruitment to the genome and de novo remodelling of chromatin. Importantly, many thyroid hormone-regulated genes are associated with this mechanism of action. Moreover, in disagreement with models depicting TR as a repressor constitutively bound to chromatin in the absence of hormone, we find little evidence for TR footprints FPs genome wide, either in the presence or absence of ligand, suggesting that TR interaction with chromatin is generally highly dynamic.

Thus, in addition to the ligand-dependent switch of transcriptional co-regulators recruited to chromatin-bound TR, we propose a model wherein TR is able to dynamically bind and increase accessibility of chromatin in a ligand-dependent manner. To understand the molecular consequences of genome-wide interaction of TR with chromatin, we mapped the DNase I accessible chromatin landscape in liver from mice treated with propylthiouracil PTU mimicking hypothyroid conditions and PTU followed by L-triiodothyronine T3 resembling hyperthyroidism.

Nuclei were purified from freshly isolated livers and treated with DNase I as previously described Small mildly digested DNA fragments liberated from accessible chromatin were purified by sucrose gradients and initially sequenced to a depth of 20—30 million tags Supplementary Table 1. Replicate concordant DNase hypersensitive sites DHS were identified as previously described 17 ; between 65, and 73, DHSs were mapped in liver from hypo and hyperthyroid animals.

Interestingly, we find thousands of regions where T3 treatment results in robust changes of chromatin accessibility Fig. Sixty-nine per cent of the changes are modest but significant remodelled DHS, Fig.

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Figure 1c illustrates representative categories of accessible regions of chromatin identified. The hormone-remodelled regions are primarily located within intronic and intergenic regions Fig. Replicate concordant DHS hotpots were identified based on two biological replicates average tag densities of DHSs from the two biological replicates are plotted.

Red and orange data points represent DHS hotspots increased in accessibility as a consequence of T3 treatment, where red marks de novo DHSs. Dark and light green represent DHS hotspots with decreased accessibility after T3 treatment, where light green marks DHS that disappears as a consequence of hormone treatment.

Black shows unchanged accessible regions. The most enriched motif is shown. The three most enriched motifs are shown. The findings shown in Fig.

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To investigate whether these remodelled regions are relevant for T3-regulated gene transcription, we identified T3-regulated genes in liver under hypo or hyperthyroid conditions. Genome-wide regulation of T3-dependent transcription was analysed by Illumina expression arrays. We found no apparent changes of chromatin accessibility of regulatory regions near Thrsp Fig. Interestingly, however; transcriptional induction of Dio1 is associated with de novo and induced remodelling of several regulatory sites near the Dio1 promoter Fig.

In fact, a significant number of T3-induced genes were associated with nearby T3-remodelled chromatin compared with T3-repressed genes Fig.

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In contrast, T3-repressed genes, such as Agxt2l1 , are more frequently associated with DHSs reduced in accessibility after T3 treatment Fig. Thus, TR regulation of gene expression was to a large extent associated with nearby remodelling, including de novo remodelling, of regulatory regions, suggesting that the transition from repressed to activated state might not simply work through a switch from co-repressor to co-activator interaction with pre-occupied TR.

In addition, co-activators and chromatin remodellers may also be recruited through ligand-dependent TR occupancy of chromatin, a mechanism shared with other steroid hormone receptors such as GR, PR and AR. Blue data points represent differentially expressed genes scored by an FDR of 0. Arrows mark DHS accessibility regulated by T3. Genes are sorted from most induced to most repressed by T3. Enriched regions for TR occupancy were subsequently identified using TR double KO as background control and a stringent cutoff criterion for peak identification.

More than twice as many ligand-facilitated TRBS were found. Two hundred TSS from random genes were chosen as background control. Genes are sorted from most induced and to most repressed by T3. Thus chromatin in liver tissue may indeed harbour a relative low number of TRBS. Importantly, similar trends are seen for ER and AR occupancy of remodelled chromatin in MCF7 and LNCaP cells, respectively 25 , inferring that low receptor occupancy of remodelled DHS is not necessarily a technical issue related to the antibody but may be associated to the dynamic behaviour of nuclear receptors see below or secondary effects of hormone treatment.

This demonstrates that hormone generally stimulates TR occupancy of chromatin, which agrees with recent reports showing hormone-facilitated recruitment of ectopically expressed TR Thus, selective TR recruitment to chromatin is determined by the strength and frequency of the response element. Here unliganded TR preferentially occupies accessible chromatin with a strong consensus motif.

Less accessible chromatin with weaker binding motifs display low occupancy by TR. Interestingly, a highly conserved motif is needed at sites where TR is able to penetrate inaccessible chromatin. Binding leads to remodelling through recruitment of co-activator complexes. Consequently, unliganded TR will not occupy these types of response elements. In contrast, T3-repressed genes show little enrichment of nearby TRBS, suggesting that liganded TR is preferentially associated with gene activation Fig. This list of genes likely constitutes direct TR targets in liver and gene ontology analysis indicates direct TR regulation of genes involved in fatty acid, steroid and cholesterol metabolism Supplementary Table 3.

Importantly, two-thirds of the T3-activated genes are associated with hormone-facilitated TR recruitment to chromatin Fig. Idh3 , Gpd2 and Pdp2 represent direct TR target genes with nearby occupancy of TR in hypothyroid condition and thus potentially actively repressed by TR in that state Fig. Activation of Gpd2 and Pdp2 transcription is not associated with considerable change of TR occupancy and chromatin is not significantly remodelled Fig.

This suggests that activation of Gpd2 and Pdp2 is coupled with co-repressor disassociation but in contrast to the bimodal switch model, co-activator pre-occupies TRBS in the absence of hormone and continues to occupy chromatin in the presence of hormone. Error bars indicate s.

Thus, Dio1 is not a candidate for considerable direct repression by TR, concretely illustrating multiple mechanisms by which thyroid hormones regulate gene expression programmes. Early studies showed that at certain sites, liganded as well as unligand TR interaction with chromatin is associated with a DNase-accessible region and a FP corresponding to TR bound directly to DNA 3. Collectively, our findings demonstrate that TR occupancy is generally not associated with a FP in chromatin and this may likely be a general phenomenon for steroid hormone receptors irrespective of their ability to repress transcription.

DNase-seq library is from livers isolated from hyperthyroid mice. Unlike steroid hormone receptors such as GR, AR and PR, unliganded TR is localized to the nucleus, where the receptor interacts with chromatin to repress transcription. Over the last two decades, transcriptional regulation by TR has been described by a model, wherein TR is bound to chromatin in the absence of ligand, recruits co-repressor complexes and represses transcription.

On ligand binding, the receptor undergoes a hormone-dependent conformational change, leading to disassociation of co-repressors and recruitment of co-activators. This model originates from early pioneering studies on steroid hormone receptors, where TR was demonstrated to interact with chromatin both in the presence and the absence of hormone 37 , Interaction was shown to be associated with increased DNase hypersensitivity and bound TR was demonstrated to FP 3 , leading to the general assumption that TR is constitutively bound to chromatin.

Subsequent identification of transcriptional co-activators and co-repressors interacting with TR led to the widely accepted co-factor switch model described above Supplementary Fig.

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This predicts that genome-wide footprinting analysis may be used to identify TREs. Unexpectedly, we find that thyroid hormone induces a considerable number of genome-wide de novo DNase hypersensitive sites harbouring putative TRBS DR4 , indicating that TR can be recruited to chromatin in a ligand-dependent manner, resulting in a DNase hypersensitive site. Importantly, we show that induced chromatin remodelling, including de novo remodelling, is associated with thyroid hormone-induced and not repressed transcription of nearby genes, demonstrating that ligand-dependent recruitment of TR and resulting chromatin remodelling are associated with thyroid hormone-activated gene transcription.

These findings collectively suggest an alternative mechanism for TR-regulated gene transcription, wherein ligand-dependent recruitment of TR to the genome can result in de novo remodelling of chromatin- and dynamic-assisted loading of transcriptional co-regulators 20 , 40 Supplementary Fig. Notably, the previously described dynamic mobility of TR in living cells 41 is also supportive of the model described here. Moreover, and in agreement with observations from other steroid hormone receptors 17 , repressed transcription as a consequence of hormone treatment is associated with nearby regions with reduced chromatin accessibility.

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These regions are not enriched for hormone receptor binding sites and are thus possibly regulated by indirect mechanisms such as transcriptional co-regulator sequestering. A recent study using TR overexpression suggested that hormone-facilitated gene repression is linked to reduced TR occupancy We do not find significant reduction of endogenous TR occupancy in response to hormone.

Although stable unliganded TR interaction with chromatin predominates in current models, several early studies indicated that TR does not necessarily FP on chromatin in the absence of ligand 44 , Lack of footprinting may be a general phenomenon for steroid hormone receptors 32 , 33 and may be credited to the highly dynamic mechanisms of their interaction with chromatin 20 , 33 , 41 , Collectively, we demonstrate that TR is recruited to chromatin by multiple mechanisms, including hormone-independent interactions with TREs for unliganded TR and ligand-induced TR recruitment to chromatin.

This leaves a very important question of how TR discriminates between these two extremes, especially in hypothyroid conditions. Motif analysis suggests that the presence and strength of the TR-binding motif DR4 within accessible chromatin is an important determinant regulating TR occupancy of chromatin in absence of T3, where unliganded TR preferentially occupy regions with strong TREs.

In contrast, when T3 is available, TR is able to occupy accessible chromatin harbouring less stringent TR-binding motifs. Here ligand-facilitated recruitment to pre-accessible chromatin may be orchestrated by cooperation with pre-bound TFs 17 , 47 , 48 , Cooperation likely requires liganded TR and will only be favourable under such conditions. Previous studies have shown that hormone changes continuous shuttling of TR between cytoplasm and nucleus as well as redistribution of TR in the nucleus 2 , Reorganization of TR may increase subnuclear TR concentration and drive hormone-dependent recruitment to specific sites of the genome.

Changing local TF concentration relative to the amount of binding sites have been shown to rewire transcriptional networks, likely determined by differential affinity of TF for its degenerated binding sequence Such hormone-sensitive TRBS may work similar to the reported glucocorticoid hypersensitive sites Interestingly, at a subset of TRBS and in the presence of T3, TR is able to penetrate an inaccessible chromatin configuration and induce de novo chromatin remodelling. Selectivity to these sites may also be driven by cooperation with other TFs, and remodelling proteins to remodel chromatin and promote TR occupancy as seen for other steroid hormone receptors such as GR 17 , 25 , 49 , Shaffer If you've read a Head First book, you know what to expect--a visually rich format designed for the way your brain works.

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