NAD Modulates DNA Methylation and Cell Differentiation.

Simone Ummarino,Bon Q Trinh,Giulia Gaggi,Lucrezia Rinaldi,Marta Borchiellini,Andy Joe Seelam,Yanzhou Zhang,Mahmoud A Bassal,Susumu S Kobayashi,Ikei S Kobayashi,Alexander K Ebralidze,Annalisa Di Ruscio,Clinton Hausman,Barbara Ghinassi

doi:10.3390/cells10112986

Abstract

Nutritional intake impacts the human epigenome by directing epigenetic pathways in normal cell development via as yet unknown molecular mechanisms. Consequently, imbalance in the nutritional intake is able to dysregulate the epigenetic profile and drive cells towards malignant transformation. Here we present a novel epigenetic effect of the essential nutrient, NAD. We demonstrate that impairment of DNMT1 enzymatic activity by NAD-promoted ADP-ribosylation leads to demethylation and transcriptional activation of the CEBPA gene, suggesting the existence of an unknown NAD-controlled region within the locus. In addition to the molecular events, NAD- treated cells exhibit significant morphological and phenotypical changes that correspond to myeloid differentiation. Collectively, these results delineate a novel role for NAD in cell differentiation, and indicate novel nutri-epigenetic strategies to regulate and control gene expression in human cells.

Highlights

Malnutrition and obesity are associated with epigenetic dysregulation, thereby promoting cellular transformation and cancer initiation [1,2]
K562, HEK293 and Jurkat cell lines were purchased from ATCC. and were grown in RPMI (K562 and Jurkat) or DMEM (HEK293) medium supplemented with 10% fetal bovine serum (FBS), in the absence of antibiotics and both at 37 ◦ C, 5% CO2
To examine whether similar effects could be mediated by NAD, K562 cells were cultured following a single addition of NAD or vehicle to the media, and tracked over four days (Figure 1a)

Summary

Introduction

Malnutrition and obesity are associated with epigenetic dysregulation, thereby promoting cellular transformation and cancer initiation [1,2]. The degree of obesity, in terms of body weight, is a well-documented risk factor for hematopoietic disease and cancer [4,5]. Together, this evidence highlights the importance of balanced micronutrient intake in order to preserve cell-specific epigenetic programming and prevent anomalies that can potentially result in malignant transformation [6,7]. Numerous studies have focused on establishing a link between nutrition and epigenetics This led to the concept of “Precision Nutrition”: a translational approach based on the use of dietary compounds to direct epigenetic changes and drive normal cellular development [8]. The molecular mechanisms by which nutrients modulate the epigenome of healthy or cancer cells is largely unknown

Methods

Results

Conclusion