The Multifaceted Roles of CHROMR in Innate Immunity, Cancer, and Cholesterol Homeostasis

Abstract

CHROMR is a primate-specific long noncoding RNA with emerging roles in homeostasis and pathophysiology. Elevated blood levels of CHROMR have been observed in patients with cardiovascular disease and several cancers, where it is correlated with poor clinical outcomes. Like many lncRNAs, CHROMR accumulates in both the nucleus and the cytoplasm, and it assumes distinct functions in each of these cellular compartments. In the nucleus, CHROMR sequesters a transcriptional repressor complex to activate interferon-stimulated gene expression and antiviral immunity. In the cytoplasm, CHROMR competitively inhibits microRNAs involved in cholesterol efflux and cell cycle regulation, thereby impacting gene pathways involved in reverse cholesterol transport, HDL biogenesis, and tumor growth. In this review, we detail the multifaceted functions of CHROMR in cholesterol metabolism, innate immunity, and cancer progression. We also explore the potential molecular mechanisms that govern its expression and dynamic subcellular localization, which may be key to its functional versatility. Advancing our understanding of the regulatory networks and cellular environments that shape CHROMR activity will be critical for assessing its promise as a therapeutic target and diagnostic biomarker.

Keywords: CHROMR; cancer; cholesterol metabolism; innate immunity; long noncoding RNA.

Figure 1

Bulk tissue gene expression of CHROMR. Violin plot detailing the expression in transcripts per million (TPM) of CHROMR in 54 different human tissues. Data are provided by the National Institutes of Health Adult Genotype Tissue Expression Project. Data are derived from RNA-seq of 17,382 samples, 948 donors (V8, August 2019).

Figure 2

CHROMR acts as a microRNA sponge and facilitates cholesterol efflux in macrophages and hepatocytes. Cytoplasmically expressed CHROMR sequesters a set of metabolic miRNAs (e.g., miR-27b, miR-33a, miR-33b, and miR-128) that in turn inhibit genes driving pathways involved in cholesterol homeostasis, including cholesterol efflux and HDL biogenesis.

Figure 3

CHROMR promotes cancer cell proliferation, metastasis, and resistance to chemotherapy. Elevated levels of CHROMR are found in stomach adenocarcinoma, diffuse large B-cell lymphoma, lung adenocarcinoma, and glioma. CHROMR can halt phosphorylation of histone deacetylases, such as HDAC3, to allow for diminished transcription of CD20, a marker of B-cell lymphomas and target for anticancer drugs (e.g., rituximab), enhancing chemotherapy resistance. In B-cell lymphoma, CHROMR acts as a competing endogenous RNA for miR-27b-3p and miR-1299, microRNAs responsible for repressing genes (CNNM1, MET) driving tumor cell proliferation and metastasis. In lung adenocarcinoma, CHROMR binds miR-186-5p to inhibit NCAPG2 to similar effects.

Figure 4

CHROMR mediates transcriptional activation of interferon-stimulated genes in macrophages. Nuclear CHROMR can bind to the IRF2/IRF2BP2 repression complex to scaffold this complex away from DNA-binding sites, allowing for the transcription of interferon-stimulated genes (ISGs) (e.g., ISG15, CXCL11).

Figure 5

In silico Hi-C profiling of the CHROMR locus in hepatic chromatin architecture. High-throughput chromosome conformation capture (Hi-C) heatmap of chromatin interactions at the genomic location (human chr2: 177,000,000–180,000,000) of CHROMR in human hepatocytes, derived from the 3D genome browser. Blue and yellow bars indicate 2 separate topologically associated domains (TADs). Black writing indicates genes on the forward strand, and blue writing indicates genes on the reverse strand.