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We have demonstrated that cytokine thymic stromal lymphopoietin (TSLP), whose expression is rapidly induced upon keratinocyteselective ablation of retinoid X receptors (RXRs) -α and -β in the mouse ($RXR\\alpha\\beta^{ep-/-} mice$), plays a key role in initiating a skin and systemic atopic dermatitis-like phenotype. We show here that topical application of the physiologically active ligand [lα,25(OH)₂D₃; calcitriol] of the vitamin D receptor, or of its low-calcemic analog MC903 (calcipotriol; Dovonex), induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome mimicking that seen in $RXR\\alpha\\beta^{ep-/-}$ mutants and transgenic mice overexpressing TSLP in keratinocytes. Furthermore, topical application of retinoic acid receptor RARγ-selective agonist BMS961 also induces TSLP expression either on its own or synergistically with lα,25-(OH)₂D₃. Our data demonstrate that RXR/ vitamin D receptor and RXR/retinoic acid receptor-γ heterodimers and their ligands cell-autonomously control the expression of TSLP in epidermal keratinocytes of the mouse. We propose molecular mechanisms through which vitamin D3 and retinoic acid signalings could be involved in the pathogenesis of atopic diseases.

To clarify the effect of retinoid X receptor-α/γ (RXR-α/γ) genes functional genetic variants (RXR-α rs4842194 G>A, RXR-γ rs100537 A>G and rs2134095 T>C) on the risk of gestational diabetes mellitus (GDM), a case–control study with 573 GDM patients and 740 pregnant women with normal glucose tolerance was performed in Guangxi area of China. An odds ratio (OR) with its corresponding 95% confidence interval (CI) was used to assess the strengths of the association between genetic variation and GDM. After adjustment of age and pre-BMI, the logistic regression analysis showed that the rs2134095 was significantly associated with GDM risk (CC vs. TT/TC: adjusted OR = 0.71, 95% CI = 0.56–0.90) in all subjects, and this result remained highly significant after Bonferroni’s correction for multiple testing (P=0.004). The stratified analysis showed that rs2134095 was significantly associated with the risk of GDM among age > 30 years (adjusted OR = 0.61, 95% CI = 0.39–0.97), BMI > 22 kg/m2 (adjusted OR = 0.46, 95% CI = 0.30–0.70), systolic blood pressure (SBP) > 120 mmHg (adjusted OR = 1.96, 95% CI = 1.14–3.36), glycosylated hemoglobin A1c (HbA1c) < 6.5% (adjusted OR = 1.41, 95% CI = 1.11–1.78), TG ≤ 1.7 mmol/l (adjusted OR = 2.57, 95% CI = 1.45–4.53), TC ≤ 5.18 mmol/l (adjusted OR = 1.58, 95% CI = 1.13–2.22), high-density lipoprotein cholesterol (HDL-c) ≤ 1.5 mmol/l (adjusted OR = 1.70, 95% CI = 1.16–2.49) and low-density lipoprotein cholesterol (LDL-c) > 3.12 mmol/l (adjusted OR = 1.47, 95% CI = 1.08–2.00) subjects, under the recessive genetic model. We also found that rs2134095 interacted with age (Pinteraction=0.039), pre-BMI (Pinteraction=0.040) and TG (Pinteraction=0.025) influencing individual’s genetic susceptibility to GDM. The rs2134095 T>C is significantly associated with the risk of GDM by effect of a single locus and/or complex joint gene–gene and gene–environment interactions. Larger sample-size and different population studies are required to confirm the findings.

The retinoid X receptors (RXRs) are ligand-activated transcription factors which heterodimerize with a number of nuclear hormone receptors, thereby controlling a variety of (patho)-physiological processes. Although synthetic RXR ligands are developed for the treatment of various diseases, endogenous ligand(s) for these receptors have not been conclusively identified. We show here that mice lacking cellular retinol binding protein (Rbp1-/-) display memory deficits reflecting compromised RXR signaling. Using HPLC-MS and chemical synthesis we identified in Rbp1-/- mice reduced levels of 9-cis-13,14-dihydroretinoic acid (9CDHRA), which acts as an RXR ligand since it binds and transactivates RXR in various assays. 9CDHRA rescues the Rbp1-/- phenotype similarly to a synthetic RXR ligand and displays similar transcriptional activity in cultured human dendritic cells. High endogenous levels of 9CDHRA in mice indicate physiological relevance of these data and that 9CDHRA acts as an endogenous RXR ligand.

Understanding how embryonic progenitors decode extrinsic signals and transform into lineage-specific regulatory networks to drive cell fate specification is a fundamental, yet challenging question. Here, we develop a new model of surface epithelium (SE) differentiation induced by human embryonic stem cells (hESCs) using retinoic acid (RA), and identify BMP4 as an essential downstream signal in this process. We show that the retinoid X receptors, RXRA and RXRB, orchestrate SE commitment by shaping lineage-specific epigenetic and transcriptomic landscapes. Moreover, we find that TCF7, as a RA effector, regulates the transition from pluripotency to SE initiation by directly silencing pluripotency genes and activating SE genes. MSX2, a downstream activator of TCF7, primes the SE chromatin accessibility landscape and activates SE genes. Our work reveals the regulatory hierarchy between key morphogens RA and BMP4 in SE development, and demonstrates how the TCF7-MSX2 axis governs SE fate, providing novel insights into RA-mediated regulatory principles.

Rexinoids are agonists of nuclear rexinoid X receptors (RXR) that heterodimerize with other nuclear receptors to regulate gene transcription. A number of selective RXR agonists have been developed for clinical use but their application has been hampered by the unwanted side effects associated with the use of rexinoids and a limited understanding of their mechanisms of action across different cell types. Our previous studies showed that treatment of organotypic human epidermis with the low toxicity UAB30 and UAB110 rexinoids resulted in increased steady-state levels of all- trans -retinoic acid (ATRA), the obligatory ligand of the RXR-RAR heterodimers. Here, we investigated the molecular mechanism underlying the increase in ATRA levels using a dominant negative RXRα that lacks the activation function 2 (AF-2) domain. The results demonstrated that overexpression of dnRXRα in human organotypic epidermis markedly reduced signaling by resident ATRA, suggesting the existence of endogenous RXR ligand, diminished the biological effects of UAB30 and UAB110 on epidermis morphology and gene expression, and nearly abolished the rexinoid-induced increase in ATRA levels. Global transcriptome analysis of dnRXRα-rafts in comparison to empty vector-transduced rafts showed that over 95% of the differentially expressed genes in rexinoid-treated rafts constitute direct or indirect ATRA-regulated genes. Thus, the biological effects of UAB30 and UAB110 are mediated through the AF-2 domain of RXRα with minimal side effects in human epidermis. As ATRA levels are known to be reduced in certain epithelial pathologies, treatment with UAB30 and UAB110 may represent a promising therapy for normalizing the endogenous ATRA concentration and signaling in epithelial tissues.

Skeletal muscles consist of fibers of differing metabolic activities and contractility, which become remodeled in response to chronic exercise, but the epigenomic basis for muscle identity and adaptation remains poorly understood. Here, we used chromatin immunoprecipitation sequencing of dimethylated histone 3 lysine 4 and acetylated histone 3 lysine 27 as well as transposase-accessible chromatin profiling to dissect cis-regulatory networks across muscle groups. We demonstrate that in vivo enhancers specify muscles in accordance with myofiber composition, show little resemblance to cultured myotube enhancers, and identify glycolytic and oxidative muscle-specific regulators. Moreover, we find that voluntary wheel running and muscle-specific peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc1a) transgenic (mTg) overexpression, which stimulate endurance performance in mice, result in markedly different changes to the epigenome. Exercise predominantly leads to enhancer hypoacetylation, whereas mTg causes hyperacetylation at different sites. Integrative analysis of regulatory regions and gene expression revealed that exercise and mTg are each associated with myocyte enhancer factor (MEF) 2 and estrogen-related receptor (ERR) signaling and transcription of genes promoting oxidative metabolism. However, exercise was additionally associated with regulation by retinoid X receptor (RXR), jun proto-oncogene (JUN), sine oculis homeobox factor (SIX), and other factors. Overall, our work defines the unique enhancer repertoires of skeletal muscles in vivo and reveals that divergent exercise-induced or PGC1α-driven epigenomic programs direct partially convergent transcriptional networks.

Aim: Polymorphisms in retinoid X receptors (RXRs) are very interesting from the point of view of a possible association of their variability with psoriasis. Methods: A total of 293 patients with plaque psoriasis, 82 patients with psoriasis guttata and 202 control subjects were enrolled in this study focused on 3 polymorphisms in RXRA and RXRB gene associations. Results: A marginally significant increase in AA allelic frequency of the RXRA A39526AA polymorphism in plaque psoriatic men compared to healthy men was proved. In women with psoriasis guttata, the higher risk for genotypes AA and TT in the RXRB 3′+140A/T polymorphism compared to healthy women was identified (p corr = 0.01). The genotypes A/A and AA/AA are more frequent in plaque psoriasis patients with a positive family history of psoriasis compared to the patients with a negative family history of psoriasis (p corr = 0.02). The A/A genotype is more frequent in patients with plaque psoriasis and repeated tonsillitis/tonsillectomy (p = 0.02). In the RXRB polymorphism, no genotype TT is observed in patients with psoriasis guttata with a positive personal history of repeated tonsillitis (p corr = 0.001). Conclusion: Individual gene characteristics of patients with psoriasis improve the possibilities of pharmacotherapy using pharmacogenomic approaches which could be further stratified in future according to the subtypes of psoriasis.

Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of the neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. Here, we elucidate how retinoid-X-receptor (RXR) nuclear receptor signaling impacts these two aspects of PD pathogenesis. We find that activated RXR differentially regulates fatty acid desaturases, significantly reducing the transcript levels of the largely brain-specific desaturase SCD5 in human cultured neural cells and PD patient-derived neurons. This was associated with reduced perilipin-2 protein levels in patient neurons, reversal of αS-induced increases in lipid droplet (LD) size, and a reduction of triglyceride levels in human cultured cells. With regard to αS proteostasis, our study reveals that RXR agonism stimulates lysosomal clearance of αS. Our data support the involvement of Polo-like kinase 2 activity and αS S129 phosphorylation in mediating this benefit. The lowering of cellular αS levels was associated with reduced cytotoxicity. Compared to RXR activation, the RXR antagonist HX531 had the opposite effects on LD size, SCD, αS turnover, and cytotoxicity, all supporting pathway specificity. Together, our findings show that RXR-activating ligands can modulate fatty acid metabolism and αS turnover to confer benefit in cellular models of PD, including patient neurons. We offer a new paradigm to investigate nuclear receptor ligands as a promising strategy for PD and related synucleinopathies.

Although lysyl oxidase-like 1 ( LOXL1 ) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis -acting effect on the expression levels of LOXL1 , mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1 , eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression. LOXL1 is a genetic risk factor for pseudoexfoliation syndrome of the eye but a causal variant has not been identified. Here, Pasutto et al ., find intronic LOXL1 risk variants influence transcription factor binding and alternative splicing of LOXL1 in affected tissues reducing levels of LOXL1 mRNA.

Adipogenesis is tightly controlled by a complex network of transcription factors acting at different stages of differentiation. Peroxisome proliferator‐activated receptor γ (PPARγ) and CCAAT/enhancer‐binding protein (C/EBP) family members are key regulators of this process. We have employed DNase I hypersensitive site analysis to investigate the genome‐wide changes in chromatin structure that accompany the binding of adipogenic transcription factors. These analyses revealed a dramatic and dynamic modulation of the chromatin landscape during the first hours of adipocyte differentiation that coincides with cooperative binding of multiple early transcription factors (including glucocorticoid receptor, retinoid X receptor, Stat5a, C/EBPβ and ‐δ) to transcription factor ‘hotspots’. Our results demonstrate that C/EBPβ marks a large number of these transcription factor ‘hotspots’ before induction of differentiation and chromatin remodelling and is required for their establishment. Furthermore, a subset of early remodelled C/EBP‐binding sites persists throughout differentiation and is later occupied by PPARγ, indicating that early C/EBP family members, in addition to their well‐established role in activation of PPARγ transcription, may act as pioneering factors for PPARγ binding. Adipogenesis is a tightly controlled differentiation process regulated by a complex transcriptional network. Here, DNase I hypersensitive site analysis, DHSseq, reveals the genome‐wide changes in chromatin structure that occur during adipogenesis and identifies sites that are bound by multiple transcription factors.