Adipose stem cells from patients with Crohn's disease show a distinctive DNA methylation pattern
Serena, Carolina (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Millan, Monica (Hospital Universitari i Politècnic La Fe (València))
Ejarque, Miriam (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Saera-Vila, Alfonso (Hospital Universitari Joan XXIII de Tarragona. Institut d'Investigació Sanitària Pere Virgili)
Maymó-Masip, Elsa (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Núñez Roa, Catalina (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Monfort-Ferré, Diandra (Hospital Universitari Joan XXIII de Tarragona. Institut d'Investigació Sanitària Pere Virgili)
Terrón-Puig, Margarida (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Bautista, Michelle (Hospital Universitari Joan XXIII de Tarragona)
Menacho, Margarita (Hospital Universitari Joan XXIII de Tarragona)
Marti-Gallostra, Marc (Hospital Universitari Vall d'Hebron)
Espin-Basany, Eloy (Hospital Universitari Vall d'Hebron)
Vendrell, Joan (Universitat Rovira i Virgili)
Fernández-Veledo, Sonia (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	Crohn's disease (CD) is characterized by persistent inflammation and ulceration of the small or large bowel, and expansion of mesenteric adipose tissue, termed creeping fat (CF). We previously demonstrated that human adipose-derived stem cells (hASCs) from CF of patients with CD exhibit dysfunctional phenotypes, including a pro-inflammatory profile, high phagocytic capacity, and weak immunosuppressive properties. Importantly, these phenotypes persist in patients in remission and are found in all adipose depots explored including subcutaneous fat. We hypothesized that changes in hASCs are a consequence of epigenetic modifications. We applied epigenome-wide profiling with a methylation array (Illumina EPIC/850k array) and gene expression analysis to explore the impact of CD on the methylation signature of hASCs isolated from the subcutaneous fat of patients with CD and healthy controls (n = 7 and 5, respectively; cohort I). Differentially methylated positions (p value cutoff < 1 × 10 −4 and ten or more DMPs per gene) and regions (inclusion threshold 0. 2, p value cutoff < 1 × 10 −2 and more than 2 DMRs per gene) were identified using dmpfinder and Bumphunter (minfi), respectively. Changes in the expression of differentially methylated genes in hASCs were validated in a second cohort (n = 10/10 inactive and active CD and 10 controls; including patients from cohort I) and also in peripheral blood mononuclear cells (PBMCs) of patients with active/inactive CD and of healthy controls (cohort III; n = 30 independent subjects). We found a distinct DNA methylation landscape in hASCs from patients with CD, leading to changes in the expression of differentially methylated genes involved in immune response, metabolic, cell differentiation, and development processes. Notably, the expression of several of these genes in hASCs and PBMCs such as tumor necrosis factor alpha (TNFA) and PR domain zinc finger protein 16 (PRDM16) were not restored to normal (healthy) levels after disease remission. hASCs of patients with CD exhibit a unique DNA methylation and gene expression profile, but the expression of several genes are only partially restored in patients with inactive CD, both in hASCs and PBMCs. Understanding how CD shapes the functionality of hASCs is critical for investigating the complex pathophysiology of this disease, as well as for the success of cell-based therapies. Human adipose-stem cells isolated from subcutaneous fat of patients with Crohn's disease exhibit an altered DNA methylation pattern and gene expression profile compared with those isolated from healthy individuals, with immune system, cell differentiation, metabolic and development processes identified as the main pathways affected. Interestingly, the gene expression of several genes involved in these pathways is only partially restored to control levels in patients with inactive Crohn's disease, both in human adipose-stem cells and peripheral blood mononuclear cells. Understanding how Crohn's disease shapes the functionality of human adipose-stem cells is critical for investigating the complex pathophysiology of this disease, as well as for the success of cell-based therapies.
Ayudas:	Ministerio de Economía y Competitividad PI18/00037 Ministerio de Economía y Competitividad PI15/00143 Ministerio de Economía y Competitividad PI14/00228 Ministerio de Economía y Competitividad PI17/01503 Ministerio de Economía y Competitividad SAF2015-65019-R Ministerio de Economía y Competitividad RTI2018-09391 Ministerio de Ciencia e Innovación RYC2013-13186 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT002/16/00120 Instituto de Salud Carlos III CM18/00029
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan aquestes es distribueixin sota la mateixa llicència que regula l'obra original i es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Methylome ; Inflammatory bowel disease ; Adipose tissue ; Epigenetics ; Gene expression
Publicado en:	Clinical Epigenetics, Vol. 12 (april 2020) , ISSN 1868-7083

DOI: 10.1186/s13148-020-00843-3
PMID: 32252817

15 p, 4.6 MB

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