J Bone Metab.  2019 Feb;26(1):3-12. 10.11005/jbm.2019.26.1.3.

The Function of the Vitamin D Receptor and a Possible Role of Enhancer RNA in Epigenomic Regulation of Target Genes: Implications for Bone Metabolism

• Sawatsubashi S
• Nishimura
• Mori J
• Kouzmenko
• Kato S

• KMID: 2440639
• DOI: http://doi.org/10.11005/jbm.2019.26.1.3

Abstract

Vitamin D (VD) is essential for bone health, and VD or its analogues are widely used in clinics to ameliorate bone loss. The targets and mode of VD anti-osteoporotic actions appear to be different from those of other classes of drugs modulating bone remodeling. VD exerts its biological activities through the nuclear VD receptor (VDR)-mediated transcriptional regulation of target mRNA and non-coding RNA genes. VD-induced gene regulation involves epigenetic modifications of chromatin conformation at the target loci as well as reconfiguration of higher-order chromosomal organization through VDR-mediated recruitment of various regulatory factors. Enhancer RNAs (eRNA), a class of non-coding enhancer-derived RNAs, have recently emerged as VDR target gene candidates that act through reorganization of chromatin looping to induce enhancer-promoter interaction in activation of mRNA-encoding genes. This review outlines the molecular mechanisms of VD actions mediated by the VDR and suggests novel function of eRNAs in VDR transactivation.

Keyword

Chromatin reorganization; Enhancer RNA; Non-coding RNA; Vitamin D; Vitamin D receptor

MeSH Terms

Bone Remodeling
Chromatin
Epigenomics*
Metabolism*
Receptors, Calcitriol*
RNA*
RNA, Messenger
RNA, Untranslated
Transcriptional Activation
Vitamin D*
Vitamins*
Chromatin
RNA
RNA, Messenger
RNA, Untranslated
Receptors, Calcitriol
Vitamin D
Vitamins

Figure

• 

  Fig. 1 Schematic representation of vitamin D signaling and its related disease. Vitamin D is converted into an active form as a vitamin D receptor (VDR) ligand for gene regulation. Deficiency of dietary vitamin D as well as genetic mutations inducing malfunction of 1α-hydroxylase and VDR causes rachitic abnormality. VDDRI, vitamin D-dependent rickets type 1; VDDRII, vitamin D-dependent rickets type 2; RXR, retinoid X receptor; VDRE, vitamin D response element; 1α,25(OH)2D3, 1α,25-dihydroxy-vitamin Dw.

• 

  Fig. 2 Schematic representation of vitamin D target genes. The target genes for vitamin D receptor (VDR) were considered to be limited to the mRNA genes encoding proteins. However, recent progress in human genome by means of the next generation DNA sequencers have uncovered that more than 80% of the human genome encode non-coding RNAs (ncRNA). As some classes of the ncRNAs are transcribed by RNA polymerase II, VDR is assumed to transcribe a set of ncRNAs as target genes. RXR, retinoid X receptor; VDRE, vitamin D response element; eRNA, enhancer RNA; IncRNA, long non-coding RNA; miRNA, microRNA.

• 

  Fig. 3 Schematic representation of chromatin reorganization and epigenetic regulators. Chromatin reorganization is achieved through histone modification and chromatin remodeling. The specific combination of histone modifications direct the state of chromatin activation. The chromatin remodelers and histone modifiers form in general multi-subunit complexes. TFTC, T cell transcription factor; TRRAP, transformation/transcription domain-associated protein; GCN5, general control of amino acid synthesis 5; OGT, O-GlcNAc transferase; MLL5, mixed lineage leukemia 5; LSD1, lysine-specific demethylase 1; RetCoR, RNA helicase DHX30; CoREST, repressor element 1 silencing transcription factor corepressor; HDM, histone demethylase; HDAC, histone deacetylase; SWI, switching defective; SNF, sucrose nonfermenting; BRG, Brahma-related gene; BRM, Brahma; NuRD, nucleosome remodelling and deacetylase.

• 

  Fig. 4 Schematic representation of enhancer RNAs (eRNAs) transcription from enhancer. One class of non-coding RNAs is eRNA, that is transcribed from strong enhancers (not all enhancers) like super enhancers. The expression levels of eRNAs are very low and the transcription start sites are multiple and ambiguous. TF, transcription factor; TAD, topologically associating domain; CTCF, CCCTC-binding factor.

• 

  Fig. 5 Property of enhancer RNAs (eRNAs). The currently known information of eRNAs is shown.

• 

  Fig. 6 Schematic representation of chromatin looping by enhancer RNAs (eRNAs) in the vitamin D receptor (VDR) target mRNA genes. Chromatin looping is stabilized by cohesion complex by aid of eRNAs for efficient transcription of the VDR target mRNA genes. POL, polymerase; RXR, retinoid X receptor; VDRE, vitamin D response element.

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