| 1. |
- Johansson, Ellen, et al.
(författare)
-
Revising the embryonic origin of thyroid C cells in mice and humans
- 2015
-
Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 142:20, s. 3519-3528
-
Tidskriftsartikel (refereegranskat)abstract
- Current understanding infers a neural crest origin of thyroid C cells, the major source of calcitonin in mammals and ancestors to neuroendocrine thyroid tumors. The concept is primarily based on investigations in quail-chick chimeras involving fate-mapping of neural crest cells to the ultimobranchial glands that regulate Ca(2+) homeostasis in birds, reptiles, amphibians and fishes, but whether mammalian C cell development implicates a homologous ontogenetic trajectory has not been experimentally verified. With lineage tracing we now provide direct evidence that Sox17+ anterior endoderm is the only source of differentiated C cells and their progenitors in mice. In similarity with many gut endoderm derivatives embryonic C cells were found to co-express pioneer factors forkhead box (Fox) a1 and Foxa2 before neuroendocrine differentiation takes place. In the ultimobranchial body epithelium emerging from pharyngeal pouch endoderm in early organogenesis differential Foxa1/Foxa2 expression distinguished two spatially separated pools of C cell precursors with different growth properties. A similar expression pattern was recapitulated in medullary thyroid carcinoma cells in vivo consistent with a growth-promoting role of Foxa1. Contrasting embryonic precursor cells, C cell-derived tumor cells invading the stromal compartment down-regulated Foxa2 foregoing epithelial-mesenchymal transition designated by loss of E-cadherin; both Foxa2 and E-cadherin were re-expressed at metastatic sites. These findings revise mammalian C cell ontogeny, expand the neuroendocrine repertoire of endoderm, and redefine the boundaries of neural crest diversification. The data further underpin distinct functions of Foxa1 and Foxa2 in both embryonic and tumor development.
|
|
| 2. |
- Mirra, P., et al.
(författare)
-
Adipocyte precursor cells from first degree relatives of type 2 diabetic patients feature changes in hsa-mir-23a-5p, -193a-5p, and -193b-5p and insulin-like growth factor 2 expression
- 2021
-
Ingår i: FASEB Journal. - 0892-6638. ; 35:4
-
Tidskriftsartikel (refereegranskat)abstract
- First-degree relatives (FDRs) of type 2 diabetics (T2D) feature dysfunction of subcutaneous adipose tissue (SAT) long before T2D onset. miRNAs have a role in adipocyte precursor cells (APC) differentiation and in adipocyte identity. Thus, impaired miRNA expression may contribute to SAT dysfunction in FDRs. In the present work, we have explored changes in miRNA expression associated with T2D family history which may affect gene expression in SAT APCs from FDRs. Small RNA-seq was performed in APCs from healthy FDRs and matched controls and omics data were validated by qPCR. Integrative analyses of APC miRNome and transcriptome from FDRs revealed down-regulated hsa-miR-23a-5p, -193a-5p and -193b-5p accompanied by up-regulated Insulin-like Growth Factor 2 (IGF2) gene which proved to be their direct target. The expression changes in these marks were associated with SAT adipocyte hypertrophy in FDRs. APCs from FDRs further demonstrated reduced capability to differentiate into adipocytes. Treatment with IGF2 protein decreased APC adipogenesis, while over-expression of hsa-miR-23a-5p, -193a-5p and -193b-5p enhanced adipogenesis by IGF2 targeting. Indeed, IGF2 increased the Wnt Family Member 10B gene expression in APCs. Down-regulation of the three miRNAs and IGF2 up-regulation was also observed in Peripheral Blood Leukocytes (PBLs) from FDRs. In conclusion, APCs from FDRs feature a specific miRNA/gene profile, which associates with SAT adipocyte hypertrophy and appears to contribute to impaired adipogenesis. PBL detection of this profile may help in identifying adipocyte hypertrophy in individuals at high risk of T2D.
|
|
| 3. |
- Parrillo, L., et al.
(författare)
-
Altered PTPRD DNA methylation associates with restricted adipogenesis in healthy first-degree relatives of Type 2 diabetes subjects
- 2020
-
Ingår i: Epigenomics. - : Future Medicine Ltd. - 1750-1911 .- 1750-192X. ; 12:10, s. 873-888
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: First-degree relatives (FDR) of individuals with Type 2 diabetes (T2D) feature restricted adipogenesis, which render them more vulnerable to T2D. Epigenetics may contribute to these abnormalities. Methods: FDR pre-adipocyte Methylome and Transcriptome were investigated by MeDIP- and RNA-Seq, respectively. Results:Methylome analysis revealed 2841 differentially methylated regions (DMR) in FDR. Most DMR localized into gene-body and were hypomethylated. The strongest hypomethylation signal was identified in an intronic-DMR at the PTPRD gene. PTPRD hypomethylation in FDR was confirmed by bisulphite sequencing and was responsible for its upregulation. Interestingly, Ptprd-overexpression in 3T3-L1 pre-adipocytes inhibited adipogenesis. Notably, the validated PTPRD-associated DMR was significantly hypomethylated in peripheral blood leukocytes from the same FDR individuals. Finally, PTPRD methylation pattern was also replicated in obese individuals. Conclusion: Our findings indicated a previously unrecognized role of PTPRD in restraining adipogenesis. This abnormality may contribute to increase FDR proclivity toward T2D.
|
|
| 4. |
- Parrillo, L., et al.
(författare)
-
Epigenetic Dysregulation of the Homeobox A5 (HOXA5) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity
- 2022
-
Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:4
-
Tidskriftsartikel (refereegranskat)abstract
- Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor Homeobox A5 (HOXA5) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate WNT-signaling activation. Importantly, in preadipocytes from FDR individuals, HOXA5 expression was attenuated, with hypermethylation of the HOXA5 promoter region found responsible for its downregulation, as revealed by luciferase assay. Both HOXA5 gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In preadipocytes from FDR, the low HOXA5 expression negatively correlated with enhanced transcription of the WNT signaling downstream genes NFATC1 and WNT2B. In silico evidence indicated that NFATC1 and WNT2B were directly controlled by HOXA5. The HOXA5 promoter region also was hypermethylated in peripheral blood leukocytes from these same FDR individuals, which was further revealed in peripheral blood leukocytes from an independent group of obese subjects. Thus, HOXA5 controlled adipogenesis in humans by suppressing WNT signaling. Altered DNA methylation of the HOXA5 promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
|
|
| 5. |
- Parrillo, L., et al.
(författare)
-
The Transcription Factor HOXA5: Novel Insights into Metabolic Diseases and Adipose Tissue Dysfunction
- 2023
-
Ingår i: Cells. ; 12:16
-
Tidskriftsartikel (refereegranskat)abstract
- The transcription factor HOXA5, from the HOX gene family, has long been studied due to its critical role in physiological activities in normal cells, such as organ development and body patterning, and pathological activities in cancer cells. Nonetheless, recent evidence supports the hypothesis of a role for HOXA5 in metabolic diseases, particularly in obesity and type 2 diabetes (T2D). In line with the current opinion that adipocyte and adipose tissue (AT) dysfunction belong to the group of primary defects in obesity, linking this condition to an increased risk of insulin resistance (IR) and T2D, the HOXA5 gene has been shown to regulate adipocyte function and AT remodeling both in humans and mice. Epigenetics adds complexity to HOXA5 gene regulation in metabolic diseases. Indeed, epigenetic mechanisms, specifically DNA methylation, influence the dynamic HOXA5 expression profile. In human AT, the DNA methylation profile at the HOXA5 gene is associated with hypertrophic obesity and an increased risk of developing T2D. Thus, an inappropriate HOXA5 gene expression may be a mechanism causing or maintaining an impaired AT function in obesity and potentially linking obesity to its associated disorders. In this review, we integrate the current evidence about the involvement of HOXA5 in regulating AT function, as well as its association with the pathogenesis of obesity and T2D. We also summarize the current knowledge on the role of DNA methylation in controlling HOXA5 expression. Moreover, considering the susceptibility of epigenetic changes to reversal through targeted interventions, we discuss the potential therapeutic value of targeting HOXA5 DNA methylation changes in the treatment of metabolic diseases.
|
|
| 6. |
- Spinelli, R., et al.
(författare)
-
ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first-degree relatives of type 2 diabetics
- 2022
-
Ingår i: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 21:3
-
Tidskriftsartikel (refereegranskat)abstract
- Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age-related subcutaneous adipose tissue (SAT) dysfunction, and increases risk of type 2 diabetes (T2D). First-degree relatives of T2D individuals (FDR) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDR more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APC from FDR and individuals with no diabetes familiarity (CTRL), ZMAT3 emerged as one of the top-ranked senescence-related genes featuring hypomethylation in FDR and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APC from FDR individuals revealed increases in multiple senescence markers compared to CTRL. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APC led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APC determined senescence and activation of the p53/p21 pathway, as observed in FDR APC. Adipogenesis was also inhibited in ZMAT3-overexpressing APC. In FDR APC, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, aging and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APC accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDR predisposition for T2D.
|
|
