Chromatin Changes at the PPAR-γ2 Promoter During Bone Marrow-Derived Multipotent Stromal Cell Culture Correlate With Loss of Gene Activation Potential

Author:

Lynch Patrick J.1,Thompson Elaine E.1,McGinnis Kathleen1,Rovira Gonzalez Yazmin I.1,Lo Surdo Jessica1,Bauer Steven R.1,Hursh Deborah A.1

Affiliation:

1. Cellular and Tissue Therapies Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, Maryland, USA

Abstract

Abstract Bone marrow-derived multipotent stromal cells (BM-MSCs) display a broad range of therapeutically valuable properties, including the capacity to form skeletal tissues and dampen immune system responses. However, to use BM-MSCs in a clinical setting, amplification is required, which may introduce epigenetic changes that affect biological properties. Here we used chromatin immunoprecipitation to compare post-translationally modified histones at a subset of gene promoters associated with developmental and environmental plasticity in BM-MSCs from multiple donors following culture expansion. At many locations, we observed localization of both transcriptionally permissive (H3K4me3) and repressive (H3K27me3) histone modifications. These chromatin signatures were consistent among BM-MSCs from multiple donors. Since promoter activity depends on the relative levels of H3K4me3 and H3K27me3, we examined the ratio of H3K4me3 to H3K27me3 (K4/K27) at promoters during culture expansion. The H3K4me3 to H3K27me3 ratios were maintained at most assayed promoters over time. The exception was the adipose-tissue specific promoter for the PPAR-γ2 isoform of PPAR-γ, which is a critical positive regulator of adipogenesis. At PPAR-γ2, we observed a change in K4/K27 levels favoring the repressed chromatin state during culture. This change correlated with diminished promoter activity in late passage cells exposed to adipogenic stimuli. In contrast to BM-MSCs and osteoblasts, lineage-restricted preadipocytes exhibited levels of H3K4me3 and H3K27me3 that favored the permissive chromatin state at PPAR-γ2. These results demonstrate that locus-specific changes in H3K4me3 and H3K27me3 levels can occur during BM-MSC culture that may affect their properties. Stem Cells 2015;33:2169–2181

Funder

U.S. Food and Drug Administration Modernizing Science Initiative and the Medical Countermeasures Initiative

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

Reference74 articles.

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