Vitamin D Switches BAF Complexes to Protect β Cells

Abstract

A primary cause of disease progression in type 2 diabetes (T2D) is β cell dysfunction due to inflammatory stress and insulin resistance. However, preventing β cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and β cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to PBAF and BAF chromatin remodeling complexes, respectively. Mechanistically, ligand promotes VDR association with PBAF to effect genome-wide changes in chromatin accessibility and enhancer landscape, resulting in an anti-inflammatory response. Importantly, pharmacological inhibition of BRD9 promotes PBAF-VDR association to restore β cell function and ameliorate hyperglycemia in murine T2D models. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning β cell survival and identifies the VDR:PBAF/BAF association as a potential therapeutic target for T2D.

Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

“…However, it is easy to envision that the accessibility profile of immortalized cells could be substantially different from that of normal cells. In addition, the interactions of VDR with different chromatin remodelers (Nurminen et al, 2018(Nurminen et al, , 2019Pereira et al, 2011;Wei et al, 2018) support the potential role of VDR as a pioneer factor.…”

“…Several studies have shown the capacity of VDR to interact with a range of TFs including PU.1 and GABPA, and with chromatin remodeling and histone modification enzymes such as BRD7 and KDM6B (Pereira et al, 2011;Seuter et al, 2017Seuter et al, , 2018Wei et al, 2018). There is some evidence that vitamin D may induce DNA methylation alterations (Doig et al, 2013;O'Brien et al, 2018).…”

High‐fat‐diet‐induced remission of diabetes in a subset of KATP‐GOF insulin‐secretory‐deficient mice

“…In addition, vitamin D has a beneficial role in pancreatic β‐cell function as well as hepatic lipid and glucose metabolism by increasing intracellular Ca +2 in insulin‐resistant states. Notably, a recent report showed that pharmacological potentiation of vitamin D receptor signalling partially restores β‐cell function and glucose homeostasis in type 2 diabetes mouse models; thus, we cannot exclude the possibility that the changes in metabolic variables and insulin sensitivity observed in K ATP ‐GOF‐R mice were promoted by differential vitamin D and calcium handling. Together, these results suggest that intermediate factors other than glucose metabolism could increase [Ca 2+ ] i and promote insulin secretion in K ATP ‐GOF‐R mice.…”

Exploring vitamin D signalling within skin cancer

“…1,25(OH) 2 D 3 acts as a high‐affinity ligand that binds to the vitamin D receptor (VDR), which is found in most cells of the body to carry out its diverse set of functions. Activated VDR controls the expression of genes by functioning as a transcription factor, and as an epigenetic regulator through its direct acetylation and control of chromatin structure via interactions with the PBAF/BAF chromatin remodelling complex (Figure ). As a liganded transcription factor, the VDR can interact with specific DNA sequences termed VDR response elements (VDREs).…”