Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity
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 ev...
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MDPI AG
2022-02-01
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| author | Luca Parrillo Rosa Spinelli Mattia Costanzo Pasqualina Florese Serena Cabaro Antonella Desiderio Immacolata Prevenzano Gregory Alexander Raciti Ulf Smith Claudia Miele Pietro Formisano Raffaele Napoli Francesco Beguinot |
| author_facet | Luca Parrillo Rosa Spinelli Mattia Costanzo Pasqualina Florese Serena Cabaro Antonella Desiderio Immacolata Prevenzano Gregory Alexander Raciti Ulf Smith Claudia Miele Pietro Formisano Raffaele Napoli Francesco Beguinot |
| author_sort | Luca Parrillo |
| collection | DOAJ |
| description | 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 <i>Homeobox A5</i> (<i>HOXA5</i>) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate <i>WNT</i>-signaling activation. Importantly, in preadipocytes from FDR individuals, <i>HOXA5</i> expression was attenuated, with hypermethylation of the <i>HOXA5</i> promoter region found responsible for its downregulation, as revealed by luciferase assay. Both <i>HOXA5</i> 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 <i>HOXA5</i> expression negatively correlated with enhanced transcription of the <i>WNT</i> signaling downstream genes <i>NFATC1</i> and <i>WNT2B</i>. In silico evidence indicated that <i>NFATC1</i> and <i>WNT2B</i> were directly controlled by <i>HOXA5</i>. The <i>HOXA5</i> 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, <i>HOXA5</i> controlled adipogenesis in humans by suppressing <i>WNT</i> signaling. Altered DNA methylation of the <i>HOXA5</i> promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals. |
| first_indexed | 2024-03-09T22:20:30Z |
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| id | doaj.art-c5fb346355f44d8097e2c7d9804d2b22 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T22:20:30Z |
| publishDate | 2022-02-01 |
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| spelling | doaj.art-c5fb346355f44d8097e2c7d9804d2b222023-11-23T19:16:05ZengMDPI AGCells2073-44092022-02-0111472810.3390/cells11040728Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human ObesityLuca Parrillo0Rosa Spinelli1Mattia Costanzo2Pasqualina Florese3Serena Cabaro4Antonella Desiderio5Immacolata Prevenzano6Gregory Alexander Raciti7Ulf Smith8Claudia Miele9Pietro Formisano10Raffaele Napoli11Francesco Beguinot12Department of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyLundberg Laboratory for Diabetes Research, Department of Molecular & Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, SwedenDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyDepartment of Translation Medicine, Federico II University of Naples, 80131 Naples, ItalyAlong 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 <i>Homeobox A5</i> (<i>HOXA5</i>) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate <i>WNT</i>-signaling activation. Importantly, in preadipocytes from FDR individuals, <i>HOXA5</i> expression was attenuated, with hypermethylation of the <i>HOXA5</i> promoter region found responsible for its downregulation, as revealed by luciferase assay. Both <i>HOXA5</i> 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 <i>HOXA5</i> expression negatively correlated with enhanced transcription of the <i>WNT</i> signaling downstream genes <i>NFATC1</i> and <i>WNT2B</i>. In silico evidence indicated that <i>NFATC1</i> and <i>WNT2B</i> were directly controlled by <i>HOXA5</i>. The <i>HOXA5</i> 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, <i>HOXA5</i> controlled adipogenesis in humans by suppressing <i>WNT</i> signaling. Altered DNA methylation of the <i>HOXA5</i> promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals.https://www.mdpi.com/2073-4409/11/4/728DNA methylationadipose tissuepreadipocyteobesitytranscription factorsT2D familiarity |
| spellingShingle | Luca Parrillo Rosa Spinelli Mattia Costanzo Pasqualina Florese Serena Cabaro Antonella Desiderio Immacolata Prevenzano Gregory Alexander Raciti Ulf Smith Claudia Miele Pietro Formisano Raffaele Napoli Francesco Beguinot Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity Cells DNA methylation adipose tissue preadipocyte obesity transcription factors T2D familiarity |
| title | Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity |
| title_full | Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity |
| title_fullStr | Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity |
| title_full_unstemmed | Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity |
| title_short | Epigenetic Dysregulation of the <i>Homeobox A5</i> (<i>HOXA5</i>) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity |
| title_sort | epigenetic dysregulation of the i homeobox a5 i i hoxa5 i gene associates with subcutaneous adipocyte hypertrophy in human obesity |
| topic | DNA methylation adipose tissue preadipocyte obesity transcription factors T2D familiarity |
| url | https://www.mdpi.com/2073-4409/11/4/728 |
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