RNA-seq analysis of hand osteoarthritis cartilage reveals a reciprocal regulation between retinoic acid and markers of cell senescence, identifying talarozole as a novel targeting strategy in hand osteoarthritis

Abstract Background Retinol (RO) and its active metabolite retinoic acid (RA) are major regulators of gene expression in vertebrates and influence various processes like organ development, cell differentiation, and immune response. To characterize a general transcriptomic response to RA-exposure in vertebrates, independent of species- and tissue-specific effects, four publicly available RNA-Seq datasets from Homo sapiens, Mus musculus, and Xenopus laevis were analyzed. To increase species and cell-type diversity we generated RNA-seq data with chicken hepatocellular carcinoma (LMH) cells. Additionally, we compared the response of LMH cells to RA and RO at different time points. Results By conducting a transcriptome meta-analysis, we identified three retinoic acid response core clusters (RARCCs) consisting of 27 interacting proteins, seven of which have not been associated with retinoids yet. Comparison of the transcriptional response of LMH cells to RO and RA exposure at different time points led to the identification of non-coding RNAs (ncRNAs) that are only differentially expressed (DE) during the early response. Conclusions We propose that these RARCCs stand on top of a common regulatory RA hierarchy among vertebrates. Based on the protein sets included in these clusters we were able to identify an RA-response cluster, a control center type cluster, and a cluster that directs cell proliferation. Concerning the comparison of the cellular response to RA and RO we conclude that ncRNAs play an underestimated role in retinoid-mediated gene regulation.

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Positive feedback between retinoic acid and 2-phospho-L-ascorbic acid trisodium salt during somatic cell reprogramming

Cell Regeneration ◽

10.1186/s13619-020-00057-1 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Mengdan Zhang ◽

Qian Li ◽

Tingting Yang ◽

Fei Meng ◽

Xiaowei Lai ◽

...

Keyword(s):

Ascorbic Acid ◽

Retinoic Acid ◽

Positive Feedback ◽

Dehydroascorbic Acid ◽

Rna Seq ◽

Somatic Cell Reprogramming ◽

Trisodium Salt ◽

Induced Pluripotent ◽

High Level ◽

Mesenchymal Epithelial Transition

AbstractRetinoic acid (RA) and 2-phospho-L-ascorbic acid trisodium salt (AscPNa) promote the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells. In the current studies, the lower abilities of RA and AscPNa to promote reprogramming in the presence of each other suggested that they may share downstream pathways at least partially. The hypothesis was further supported by the RNA-seq analysis which demonstrated a high-level overlap between RA-activated and AscPNa activated genes during reprogramming. In addition, RA upregulated Glut1/3, facilitated the membrane transportation of dehydroascorbic acid, the oxidized form of L-ascorbic acid, and subsequently maintained intracellular L-ascorbic acid at higher level and for longer time. On the other hand, AscPNa facilitated the mesenchymal-epithelial transition during reprogramming, downregulated key mesenchymal transcriptional factors like Zeb1 and Twist1, subsequently suppressed the expression of Cyp26a1/b1 which mediates the metabolism of RA, and sustained the intracellular level of RA. Furthermore, the different abilities of RA and AscPNa to induce mesenchymal-epithelial transition, pluripotency, and neuronal differentiation explain their complex contribution to reprogramming when used individually or in combination. Therefore, the current studies identified a positive feedback between RA and AscPNa, or possibility between vitamin A and C, and further explored their contributions to reprogramming.

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Differential RA responsiveness among subsets of mouse late progenitor spermatogonia

Reproduction ◽

10.1530/rep-21-0031 ◽

2021 ◽

Author(s):

Shinnosuke Suzuki ◽

John R. McCarrey ◽

Brian P Hermann

Keyword(s):

Stem Cells ◽

Retinoic Acid ◽

Single Cell ◽

Adult Mouse ◽

Retinoic Acid Receptor ◽

Mouse Testis ◽

Rna Seq ◽

Reporter Expression ◽

Acid Receptor ◽

Whole Mount

Initiation of spermatogonial differentiation in the mouse testis begins with the response to retinoic acid (RA) characterized by activation of KIT and STRA8 expression. In the adult, spermatogonial differentiation is spatiotemporally coordinated by a pulse of RA every 8.6 days that is localized to stages VII-VIII of the seminiferous epithelial cycle. Dogmatically, progenitor spermatogonia that express retinoic acid receptor gamma (RARG) at these stages will differentiate in response to RA, but this has yet to be tested functionally. Previous single-cell RNA-seq data identified phenotypically and functionally distinct subsets of spermatogonial stem cells (SSCs) and progenitor spermatogonia, where late progenitor spermatogonia were defined by expression of RARG and Dppa3. Here, we found late progenitor spermatogonia (RARGhigh KIT-) were further divisible into two subpopulations based on Dppa3 reporter expression (Dppa3-ECFP or Dppa3-EGFP) and were observed across all stages of the seminiferous epithelial cycle. However, nearly all Dppa3+ spermatogonia were differentiating (KIT+) late in the seminiferous epithelial cycle (stages X-XII), while Dppa3- late progenitors remained abundant, suggesting that Dppa3+ and Dppa3- late progenitors differentially responded to RA. Following acute RA treatment (2-4hr), significantly more Dppa3+ late progenitors induced KIT, including at the midpoint of the cycle (stages VI-IX), than Dppa3- late progenitors. Subsequently, single-cell analyses indicated a subset of Dppa3+ late progenitors expressed higher levels of Rxra, which we confirmed by RXRA whole-mount immunostaining. Together, these results indicate RARG alone is insufficient to initiate a spermatogonial response to RA in the adult mouse testis and suggest differential RXRA expression may discriminate responding cells.

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Human Interferon Action: Reciprocal Regulation by Retinoic Acid and β-Carotene2

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/70.5.833 ◽

1983 ◽

Keyword(s):

Retinoic Acid ◽

Human Interferon ◽

Reciprocal Regulation ◽

Β Carotene

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Differentiation-inducing and anti-proliferative activities of isoliquiritigenin and all-trans-retinoic acid on B16F0 melanoma cells: Mechanisms profiling by RNA-seq

Gene ◽

10.1016/j.gene.2016.07.052 ◽

2016 ◽

Vol 592 (1) ◽

pp. 86-98 ◽

Cited By ~ 12

Author(s):

Xiaoyu Chen ◽

Ming Yang ◽

Wenjin Hao ◽

Jichun Han ◽

Jun Ma ◽

...

Keyword(s):

Retinoic Acid ◽

Melanoma Cells ◽

Rna Seq ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Is Retinoic acid a target in hand osteoarthritis?

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2017.02.003 ◽

2017 ◽

Vol 25 ◽

pp. S1

Author(s):

H. Jonsson

Keyword(s):

Retinoic Acid ◽

Hand Osteoarthritis

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Crosstalk between Nitric Oxide and Retinoic Acid pathways is essential for amphioxus pharynx development

10.1101/2020.06.22.164632 ◽

2020 ◽

Author(s):

F Caccavale ◽

G Annona ◽

L Subirana ◽

H Escriva ◽

S Bertrand ◽

...

Keyword(s):

Nitric Oxide ◽

Transcriptional Regulation ◽

Retinoic Acid ◽

Signaling Pathways ◽

The Other ◽

Vertebrate Development ◽

Reciprocal Regulation ◽

Axial Patterning ◽

Response Elements ◽

Complex Interactions

AbstractDuring animal ontogenesis, body axis patterning is finely regulated by complex interactions between several signaling pathways. Nitric Oxide (NO) and Retinoic Acid (RA) are potent morphogens that play a pivotal role in vertebrate development. Their involvement in axial patterning of head and pharynx shows conserved features in the chordate phylum. Indeed, in the cephalochordate amphioxus NO and RA are crucial for the correct development of pharyngeal structures. Here we demonstrate the functional cooperation between NO and RA occurring in amphioxus embryogenesis. During neurulation, NO modulates RA production through the transcriptional regulation of Aldh1a.2 that irreversibly converts retinaldehyde into RA. On the other hand, RA regulates the transcription of Nos genes, probably through RA Response Elements found in their regulatory regions. The reciprocal regulation of NO and RA pathways results to be essential for the normal pharyngeal development in amphioxus and suggests that this regulatory crosstalk could be conserved in vertebrates.

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Lysosomal-Immune Axis Is Associated with COVID 19 Disease Severity: Insights from Patient Single Cell Data

10.1101/2021.01.27.428394 ◽

2021 ◽

Author(s):

Rahul Pande ◽

Erin Teeple ◽

Weixiao Huang ◽

Katherine W. Klinger ◽

Deepak Rajpal ◽

...

Keyword(s):

Single Cell ◽

Disease Severity ◽

Drug Targeting ◽

Rna Seq ◽

Network Approach ◽

Immune Pathways ◽

Novel Drug ◽

Cell Data ◽

Targeting Strategy

AbstractSARS-COV-2 has become a leading cause of illness, hospitalizations, and deaths worldwide yet heterogeneity in disease morbidity remains a conundrum. In this study, we analyzed publicly available single-cell RNA-seq data from 75076 cells sequenced from clinically staged COVID-19 patients using a network approach and identified lysosomal-immune axis as a factor significantly associated with disease severity. Our results suggest modulation of lysosomal-immune pathways may present a novel drug-targeting strategy to attenuate SARS-Cov-2 infections.

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Retinoic Acid Receptor γ1 (RARγ1) Levels Control RARβ2 Expression in SK-N-BE2(c) Neuroblastoma Cells and Regulate a Differentiation-Apoptosis Switch

Molecular and Cellular Biology ◽

10.1128/mcb.18.11.6482 ◽

1998 ◽

Vol 18 (11) ◽

pp. 6482-6492 ◽

Cited By ~ 26

Author(s):

Nicoletta Ferrari ◽

Magnus Pfahl ◽

Giovanni Levi

Keyword(s):

Retinoic Acid ◽

Morphological Changes ◽

Retinoic Acid Receptor ◽

Neuroblastoma Cells ◽

Constitutive Expression ◽

Cell Types ◽

Regulation Of Expression ◽

Reciprocal Regulation ◽

Regulatory Processes ◽

Spatio Temporal

ABSTRACT Vitamin A and its derivatives (retinoids) have profound effects on the proliferation and differentiation of many cell types and are involved in a diverse array of developmental and physiological regulatory processes, including those responsible for the development of the mature nervous system. Retinoid signals are mediated by retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs), which show distinct spatio-temporal patterns of expression during development and in adult tissues. We have used SK-N-BE2(c) neuroblastoma cells to study the effects of reciprocal regulation of expression of various RARs. We show that in these cells RARγ1 acts as a repressor of RARβ2 transcription in the absence of an agonist. In the presence of RA, the expression of RARγ1 is reduced and that of RARβ2 is induced. Overexpression of RARγ1 neutralizes the effects of RA on RARβ induction. Expression of an RARγ1-specific antisense construct leads to the constitutive expression of RARβ2. Although both overexpression of RARγ1 and its reduction of expression can result in inhibition of cell proliferation, they induce different morphological changes. Reduction of RARγ1 (and induction of RARβ) leads to increased apoptosis, whereas RARγ1 overexpression leads to differentiation in the absence of apoptosis. Thus, RARγ1 appears to control a differentiation-apoptosis switch in SK-N-BE2(c) neuroblastoma cells.

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