Vitamin D and Systems Biology

Abstract

The biological actions of the vitamin D receptor (VDR) have been investigated intensively for over 100 years and has led to the identification of significant insights into the repertoire of its biological actions. These were initially established to be centered on the regulation of calcium transport in the colon and deposition in bone. Beyond these well-known calcemic roles, other roles have emerged in the regulation of cell differentiation processes and have an impact on metabolism. The purpose of the current review is to consider where applying systems biology (SB) approaches may begin to generate a more precise understanding of where the VDR is, and is not, biologically impactful. Two SB approaches have been developed and begun to reveal insight into VDR biological functions. In a top-down SB approach genome-wide scale data are statistically analyzed, and from which a role for the VDR emerges in terms of being a hub in a biological network. Such approaches have confirmed significant roles, for example, in myeloid differentiation and the control of inflammation and innate immunity. In a bottom-up SB approach, current biological understanding is built into a kinetic model which is then applied to existing biological data to explain the function and identify unknown behavior. To date, this has not been applied to the VDR, but has to the related ERα and identified previously unknown mechanisms of control. One arena where applying top-down and bottom-up SB approaches may be informative is in the setting of prostate cancer health disparities.

Keywords: cell differentiation; prostate cancer; systems biology; vitamin D receptor.

Figure 1

A workflow for top-down and bottoms-up system biology (SB) approaches to address prostate cancer health disparities. For top-down SB there is a plethora of high dimensional data including germline structural variants, population characteristics as serum-borne, and other clinical data that can be integrated through a range of approaches to deliver insights into how the prostate could either be either sensitive or resistant to the growth restraint properties of the VDR. From the bottoms-up perspective, more focused kinetic models can be developed for how the VDR functions and is disrupted between normal and tumor cells. Combining these approaches has the potential to develop a holistic understanding of how the VDR functions in the prostate gland and how this is impacted by genomic ancestry.