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. 2017 Oct 24;10(1):168.
doi: 10.1186/s13045-017-0526-8.

A comprehensive data mining study shows that most nuclear receptors act as newly proposed homeostasis-associated molecular pattern receptors

Luqiao Wang  1   2   3 , Gayani Nanayakkara  4 , Qian Yang  4   5 , Hongmei Tan  6 , Charles Drummer  4 , Yu Sun  2 , Ying Shao  4 , Hangfei Fu  2 , Ramon Cueto  2 , Huimin Shan  2 , Teodoro Bottiglieri  7 , Ya-Feng Li  4 , Candice Johnson  4 , William Y Yang  2 , Fan Yang  2 , Yanjie Xu  1 , Hang Xi  2 , Weiqing Liu  3 , Jun Yu  2   8 , Eric T Choi  2   9 , Xiaoshu Cheng  10 , Hong Wang  2   4 , Xiaofeng Yang  11   12   13
Affiliations

A comprehensive data mining study shows that most nuclear receptors act as newly proposed homeostasis-associated molecular pattern receptors

Luqiao Wang et al. J Hematol Oncol. .

Abstract

Background: Nuclear receptors (NRs) can regulate gene expression; therefore, they are classified as transcription factors. Despite the extensive research carried out on NRs, still several issues including (1) the expression profile of NRs in human tissues, (2) how the NR expression is modulated during atherosclerosis and metabolic diseases, and (3) the overview of the role of NRs in inflammatory conditions are not fully understood.

Methods: To determine whether and how the expression of NRs are regulated in physiological/pathological conditions, we took an experimental database analysis to determine expression of all 48 known NRs in 21 human and 17 murine tissues as well as in pathological conditions.

Results: We made the following significant findings: (1) NRs are differentially expressed in tissues, which may be under regulation by oxygen sensors, angiogenesis pathway, stem cell master regulators, inflammasomes, and tissue hypo-/hypermethylation indexes; (2) NR sequence mutations are associated with increased risks for development of cancers and metabolic, cardiovascular, and autoimmune diseases; (3) NRs have less tendency to be upregulated than downregulated in cancers, and autoimmune and metabolic diseases, which may be regulated by inflammation pathways and mitochondrial energy enzymes; and (4) the innate immune sensor inflammasome/caspase-1 pathway regulates the expression of most NRs.

Conclusions: Based on our findings, we propose a new paradigm that most nuclear receptors are anti-inflammatory homeostasis-associated molecular pattern receptors (HAMPRs). Our results have provided a novel insight on NRs as therapeutic targets in metabolic diseases, inflammations, and malignancies.

Keywords: Atherosclerosis; Cardiovascular disease; Homeostasis-associated molecular pattern receptors; Metabolic disease; Nuclear receptors (NRs).

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Figures

Fig. 1
Fig. 1
Flow chart of database mining strategy and two parts of data organization. Part1: shows the database mining strategy utilized to generate tissue nuclear receptor expression profile. Part 2: the strategy utilized to measure nuclear receptor expression in human and mouse metabolic diseases. Parts 3 and 4: shows the strategy that is used to analyze the microarray data sets and identifying nuclear receptors as homeostasis-associated molecular pattern receptors (HAMPRs)
Fig. 2
Fig. 2
Our newly proposed “nuclear receptor pyramid” model in humans and mice constructed based on the number of variety of nuclear receptors expressed in tissues. n: the number of highly expressed nuclear receptors. Based on the numbers of NRs expressed in tissues, we classified tissues examined into three categories: high variety (expressed NRs n ≥ 10; n = numbers of the highly expressed NRs), moderate variety (expressed NRs 5 ≤ n < 10), and low variety (expressed 4 ≤ n) in a new nuclear receptor pyramid model in humans and high variety (expressed NRs n ≥ 7; n = numbers of the highly expressed NRs), moderate variety (expressed NRs 3 ≤ n < 7), and low variety (expressed NRs n < 3) in a new nuclear receptor pyramid model in mice
Fig. 3
Fig. 3
Oxygen sensors, VEGF pathway regulators, and stem cell master regulators may regulate nuclear receptor expression in human tissues (tissues: adipose, brain, eye, heart, kidney, liver, lymph node, muscle, pancreas, skin, spleen). a Highly expressed nuclear receptors in 11 tissues were strongly associated with angiogenic gene expression. b Correlation between highly expressed nuclear receptors and gene that regulate oxygen sensing, angiogenesis, and stem cells. c Correlation tiers between genes of interests and nuclear receptor expression in tissues. Abbreviations: PHD2: prolyl hydroxylase domain-containing protein 2; HIF1B: hypoxia-inducible factor-1 beta; HIF1/2A: hypoxia-inducible factor 1/2-alpha; VEGFA/B/C: vascular endothelial growth factor A/B/C; FIGF: C-fos-induced growth factor; FLT1/4: Fms related tyrosine kinase ¼; KDR: kinase insert domain receptor; MYC: MYC proto-oncogene; KIT: KIT proto-oncogene receptor tyrosine kinase; KLF4: Kruppel-like factor 4; POU5F1: POU class 5 homeobox 1; SOX2: SRY-box 2
Fig. 4
Fig. 4
NLRs/inflammasome sensors may be either upstream regulators or downstream targets of nuclear receptors in human tissues (tissues: adipose, brain, eye, heart, kidney, liver, lymph node, muscle, pancreas, skin, spleen). a Correlation between inflammasome genes and highly expressed nuclear receptors. b Different correlation tiers show the level of statistically significant correlation between inflammasome genes and highly expressed nuclear receptors. Abbreviations: NOD1/2/3/4: nucleotide-binding oligomerization domain-like receptors 1/2/3/4; NALP2/3/6/9/14: NLR family pyrin domain containing 2/3/6/9/14; NAIP: NLR family apoptosis inhibitory protein; NLRC4: NLR family CARD domain containing 4; ASC: PYD and CARD domain containing; IFI16: interferon gamma-inducible protein 16; CARD8: caspase recruitment domain family member 8
Fig. 5
Fig. 5
Tissue methylation status may determine the expression level of nuclear receptors in mouse tissues (tissues: mouse tissues: liver, brain, heart, kidney, lung, and spleen). a Correlation between nuclear receptors and hypomethylation status of the mouse tissues. b Different correlation tiers that depict the degree of association between hypomethylation status and nuclear receptor expression in mouse tissues. c Correlation between nuclear receptor expression and hypermethylation status of the mouse tissues. d Correlation tiers of hypermethylation status of the mouse tissues and nuclear receptor expression
Fig. 6
Fig. 6
Venn analysis of significantly changed nuclear receptor expression among four different tissues. a, b Venn diagram shows the number of significantly upregulated and downregulated nuclear receptors in four different pathologies respectively (blue, yellow, green and red represent rheumatoid arthritis/ familial hypercholesterolemia/diabetes/obesity). c The nuclear receptor genes that are upregulated, downregulated, and without any expression changes in four pathologies of interest. d The signaling pathways that are regulated by nuclear receptor genes that are upregulated, downregulated, and have no expression changes in four pathologies of interest. e A list of nuclear receptors that can be used as biomarkers to detect indicated pathologies
Fig. 7
Fig. 7
a–c Newly proposed working model which describes that most of the nuclear receptors can be classified as a family of homeostasis-associated molecular pattern receptors
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