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Regulation of all-trans retinoic acid (ATRA) signaling is crucial to early embryonic development. Embryonic stem (ES) cell-derived gastruloids mimic normal development in response to the Wnt/β-catenin agonist CHIR9901, and this study has examined the importance of the activities of RAR (retinoic acid receptor) α and γ to gastruloid development. Expression of retinoic acid receptor (RAR)γ within developing gastruloids was spatially restricted to primitive cells that co-expressed ES cell and early progenitor cell markers, i.e., Nanog, Sox2, and Oct4. In contrast, RARα expression was ubiquitous. mRNAs for the key enzymes involved in ATRA synthesis (Aldh1a2) and degradation (Cyp26a1) were not seen in cells that expressed RARγ. Treatment of ES cell-derived gastruloids with physiologically relevant (10 nm) levels of ATRA or with a highly selective RARγ agonist blocked normal developmental processes, preventing symmetry-breaking and axial elongation. This was not seen following treatments with an RARα agonist, where there was a tendency for enhanced axial elongation. Brachyury (TBXT) immuno-positive cells localized in the posterior end of elongated gastruloids in control- and RARα agonist-treated cultures, with Sox2 immuno-positive cells seen more widely, whilst both TBXT and Sox2 immuno-positive cells were randomly distributed throughout ATRA- and RARγ agonist-treated gastruloids. Concurrent treatment of gastruloids with 10 nm ATRA and 100 nm of an RARγ antagonist partially abrogated the ATRA-mediated block to axial elongation. Conversely, 10 nm RARγ antagonist treatments were associated with the formation of multi-axis gastruloid elongations, with comparatively little effect seen after treatments with an RARα antagonist. These findings reveal that RARγ plays a crucial role in the development of embryonic tissues.

Background Acute myeloid leukemia (AML) remains a challenging disease with a poor prognosis, necessitating more personalized therapeutic strategies. Retinoic acid receptor (RAR) activation is crucial for myeloid differentiation, but non-APL AML cells resist differentiation induced by the pan-RAR agonist all-trans retinoic acid (ATRA). Am80 (tamibarotene), a specific RARA agonist, has been reported to partially overcome this resistance in AML with high RARA expression. However, its effects on myeloid differentiation, especially in comparison to ATRA, remain understudied. Methods In this study we compared the effects of Am80 and ATRA in non-APL AML samples, focusing on subsets with high RARA and/or RARG expression, using molecular and phenotypic differentiation assessments. Results In contrast to previous findings, Am80 showed no advantage over ATRA in inducing differentiation in AML cell lines or primary samples, regardless of RARA and RARG expression levels. Cotreatment with inhibitors of the epigenetic modifiers LSD1 and GCN5, which facilitates retinoid-induced myeloid differentiation, enhanced the effects of both Am80 and ATRA to the same extent, with more pronounced responses observed in RARA-high samples. Gene expression analysis revealed identical molecular responses to Am80 and ATRA. Conclusions The study provides evidence that ATRA can be substituted by the more stable Am80 in retinoid-based AML therapies. It also identifies elevated RARA expression as a potential marker for sensitivity to combination therapy with retinoids and epigenetic inhibitors in AML.

Pregnancy critically depends on the transformation of the human endometrium into a decidual matrix that controls embryo implantation and placenta formation, a process driven foremost by differentiation and polarization of endometrial stromal cells into mature and senescent decidual cells. Perturbations in the decidual process underpin a spectrum of prevalent reproductive disorders, including implantation failure and early pregnancy loss, emphasizing the need for new therapeutic interventions. Resveratrol is a naturally occurring polyphenol, widely used for its antioxidant and anti-inflammatory properties. Using primary human endometrial stromal cell (HESC) cultures, we demonstrate that resveratrol has anti-deciduogenic properties, repressing not only the induction of the decidual marker genes PRL and IGFBP1 but also abrogating decidual senescence. Knockdown of Sirtuin 1, a histone deacetylase activated by resveratrol, restored the expression of IGFBP1 but not the induction of PRL or senescence markers in decidualizing HESCs, suggesting involvement of other pathways. We demonstrate that resveratrol interferes with the reprogramming of the retinoic acid signaling pathway in decidualizing HESCs by accelerating down-regulation of cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor (RAR). Notably, knockdown of CRABP2 or RAR in HESCs was sufficient to recapitulate the anti-deciduogenic effects of resveratrol. Thus, while resveratrol has been advanced as a potential fertility drug, our results indicate it may have detrimental effects on embryo implantation by interfering with decidual remodeling of the endometrium.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.

CDK4/6 inhibitors (CDK4/6i) have shown striking clinical potential in hormone receptor-positive breast cancers (BC) and endometrial cancers (EC), whereas resistance hinders their clinical utilization. The role of epigenetic alterations in CDK4/6i resistance remains poorly elucidated. Herein, through a comprehensive analysis of transcriptomic and chromatin profiles in 16 EC tissues and cell-based resistance models, we delineate the super-enhancer (SE) landscape and identify aldehyde dehydrogenase 1 family member A1 ( ALDH1A1 ) as a SE-driven gene closely associated with CDK4/6i resistance. ALDH1A1 inhibition increases susceptibility to CDK4/6i in multiple EC and BC models. Mechanistically, we demonstrate that ALDH1A1 promotes vitamin A (vitA) metabolism and induces the accumulation of its downstream metabolite, retinoic acid (RA), in resistant cells. In return, the elevated RA potentiates the interaction between retinoic acid receptor alpha (RARα) and estrogen receptor alpha (ERα) in the nucleus and facilitates RARα/ERα-occupied SE-driven transcriptional activation of ALDH1A1 , establishing a positive feedback loop that promotes CDK4/6i resistance. These findings highlight the crucial role of vitA metabolism in the epigenetic transcriptional program associated with CDK4/6i resistance, suggesting that avoiding high vitA intake or inhibiting the ALDH1A1-RA axis may be effective strategies to overcome this challenge. CDK4/6 inhibitors response is limited by frequent resistance in hormone receptor– positive cancers. Here, the authors show that a super enhancer driven increase in aldehyde dehydrogenase creates a vitamin A/retinoic acid feedback loop that promotes resistance in breast and endometrial cancer.

Homeostatic synaptic plasticity is a stabilizing mechanism engaged by neural circuits in response to prolonged perturbation of network activity. The non-Hebbian nature of homeostatic synaptic plasticity is thought to contribute to network stability by preventing “runaway” Hebbian plasticity at individual synapses. However, whether blocking homeostatic synaptic plasticity indeed induces runaway Hebbian plasticity in an intact neural circuit has not been explored. Furthermore, how compromised homeostatic synaptic plasticity impacts animal learning remains unclear. Here, we show in mice that the experience of an enriched environment (EE) engaged homeostatic synaptic plasticity in hippocampal circuits, thereby reducing excitatory synaptic transmission. This process required RARα, a nuclear retinoic acid receptor that doubles as a cytoplasmic retinoic acid-induced postsynaptic regulator of protein synthesis. Blocking RARα-dependent homeostatic synaptic plasticity during an EE experience by ablating RARα signaling induced runaway Hebbian plasticity, as evidenced by greatly enhanced long-term potentiation (LTP). As a consequence, RARα deletion in hippocampal circuits during an EE experience resulted in enhanced spatial learning but suppressed learning flexibility. In the absence of RARα, moreover, EE experience superactivated mammalian target of rapamycin (mTOR) signaling, causing a shift in protein translation that enhanced the expression levels of AMPA-type glutamate receptors. Treatment of mice with the mTOR inhibitor rapamycin during an EE experience not only restored normal AMPA-receptor expression levels but also reversed the increases in runaway Hebbian plasticity and learning after hippocampal RARα deletion. Thus, our findings reveal an RARα- and mTOR-dependent mechanism by which homeostatic plasticity controls Hebbian plasticity and learning.

Acrylamide (ACR) is an environmental reproductive toxicant with unclear testicular toxicity mechanisms. Retinoids are a group of vitamin A-related compounds that function by activating retinoid receptors. We aimed in this study to further explore All-trans retinoic acid’s (ATRA) protective response against an acrylamide-induced testicular insult model and the underlying possible mechanisms. Fifty male rats were allocated into control, DMSO, ACR (40 mg/kg bwt, i.p. daily for 14 days), ATRA (7.5 mg/kg bwt, i.p. daily), and ACR + ATRA groups. Body and testes weights, sperm parameters, testosterone level, and lactate dehydrogenase-X (LDH-X) activity were measured. In addition, testicular levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), caspase-3, Bax, and Bcl-2 were determined. Also, tissues were examined for histopathologic changes and immune expression of retinoic acid receptor-alpha (RAR-α). ACR exposure led to reduced body and testicular weights, impaired sperm parameters, and suppressed reproductive hormones (testosterone, FSH, LH). Testicular LDH-X activity decreased, along with reduced testicular RAR-α expression. Oxidative stress resulted in GSH depletion, reduced CAT and SOD activities, and increased MDA. ACR also triggered inflammation and apoptosis, with elevated TNF-α, IL-1β, IL-6, caspase-3, Bax. In contrast, ATRA improved sperm parameters and levels of hormones, restored RAR-α expression, mitigated oxidative stress, and decreased inflammation and apoptosis markers. Morphometric and histopathologic studies supported these biochemical observations. Overall, RAR-α agonist (ATRA) is linked to attenuation against ACR-induced testicular damage, along with a reduction in oxidative stress, inflammation, and cell death. These findings suggest that retinoid signaling might serve as a possible therapeutic target for reproductive toxicities induced by ACR, necessitating further mechanistic exploration.

BackgroundThe esophagus is known to be derived from the foregut. However, the mechanisms regulating this process remain unclear. In particular, the details of the human esophagus itself have been poorly researched. In this decade, studies using human induced pluripotent stem cells (hiPSCs) have proven powerful tools for clarifying the developmental biology of various human organs. Several studies using hiPSCs have demonstrated that retinoic acid (RA) signaling promotes the differentiation of foregut into tissues such as lung and pancreas. However, the effect of RA signaling on the differentiation of foregut into esophagus remains unclear. MethodsWe established a novel stepwise protocol with transwell culture and an air–liquid interface system for esophageal epithelial cell (EEC) differentiation from hiPSCs. We then evaluated the effect of all-trans retinoic acid (ATRA), which is a retinoic acid receptor (RAR)α, RARβ and RARγ agonist, on the differentiation from the hiPSC-derived foregut. Finally, to identify which RAR subtype was involved in the differentiation, we used synthetic agonists and antagonists of RARα and RARγ, which are known to be expressed in esophagus.ResultsWe successfully generated stratified layers of cells expressing EEC marker genes that were positive for lugol staining. The enhancing effect of ATRA on EEC differentiation was clearly demonstrated with quantitative reverse transcription polymerase chain reaction, immunohistology, lugol-staining and RNA sequencing analyses. RARγ agonist and antagonist enhanced and suppressed EEC differentiation, respectively. RARα agonist had no effect on the differentiation.ConclusionWe revealed that RARγ activation promotes the differentiation of hiPSCs-derived foregut into EECs.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin lymphoma originating in the skin and invading the systemic hematopoietic system. Current treatments, including chemotherapy and monoclonal antibodies yielded limited responses with high incidence of side effects, highlighting the need for targeted therapy. Screening with small inhibitors library, herein we identify cyclin dependent kinase 9 (CDK9) as a driver of CTCL growth. Single-cell RNA-seq analysis reveals a CDK9 high malignant T cell cluster with a unique actively proliferating feature. Inhibition, depletion or proteolysis targeting chimera (PROTAC)-mediated degradation of CDK9 significantly reduces CTCL cell growth in vitro and in murine models. CDK9 also promotes degradation of retinoic acid receptor α (RARα) via recruiting the E3 ligase HUWE1. Co-administration of CDK9-PROTAC (GT-02897) with all-trans retinoic acid (ATRA) leads to synergistic attenuation of tumor growth in vitro and in xenograft models, providing a potential translational treatment for complete eradication of CTCL. Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma that affects the skin. Here authors show that CDK9 degradation of retinoic acid receptor α is a vulnerability for CTCL and develop a degrader targeting CDK9 that synergizes with all-trans retinoic acid to reduce CTCL tumor growth.

Half of estrogen receptor-positive breast cancers contain a subpopulation of cytokeratin 5 (CK5)-expressing cells that are therapy resistant and exhibit increased cancer stem cell (CSC) properties. We and others have demonstrated that progesterone (P4) increases CK5+ breast cancer cells. We previously discovered that retinoids block P4 induction of CK5+ cells. Here we investigated the mechanisms by which progesterone receptors (PR) and retinoic acid receptors (RAR) regulate CK5 expression and breast CSC activity. After P4 treatment, sorted CK5+ compared to CK5− cells were more tumorigenic in vivo . In vitro , P4-treated breast cancer cells formed larger mammospheres and silencing of CK5 using small hairpin RNA abolished this P4-dependent increase in mammosphere size. Retinoic acid (RA) treatment blocked the P4 increase in CK5+ cells and prevented the P4 increase in mammosphere size. Dual small interfering RNA (siRNA) silencing of RARα and RARγ reversed RA blockade of P4-induced CK5. Using promoter deletion analysis, we identified a region 1.1 kb upstream of the CK5 transcriptional start site that is necessary for P4 activation and contains a putative progesterone response element (PRE). We confirmed by chromatin immunoprecipitation that P4 recruits PR to the CK5 promoter near the −1.1 kb essential PRE, and also to a proximal region near −130 bp that contains PRE half-sites and a RA response element (RARE). RA induced loss of PR binding only at the proximal site. Interestingly, RARα was recruited to the −1.1 kb PRE and the −130 bp PRE/RARE regions with P4, but not RA alone or RA plus P4. Treatment of breast cancer xenografts in vivo with the retinoid fenretinide reduced the accumulation of CK5+ cells during estrogen depletion. This reduction, together with the inhibition of CK5+ cell expansion through RAR/PR cross talk, may explain the efficacy of retinoids in prevention of some breast cancer recurrences.