What is the function of the MIR181A1HG gene?

MIR181A1HG Gene Function

MIR181A1HG is a long noncoding RNA (lncRNA) that serves as the host gene for microRNAs miR-181a1 and miR-181b1, and functions primarily as a regulator of vascular inflammation, immune responses, and cancer metastasis through multiple molecular mechanisms.

Primary Molecular Classification

MIR181A1HG is classified as a long noncoding RNA (lncRNA), defined as a non-messenger RNA transcript exceeding 200 nucleotides in length that lacks an open reading frame and does not code for proteins 1. These longer noncoding transcripts exert regulatory functions by interacting with other RNAs, proteins, or specific DNA sequences, often in a modular fashion allowing for multiple specific interactions 1.

Key Biological Functions

Vascular Inflammation and Atherosclerosis

MIR181A1HG acts as a central driver of vascular inflammation in atherosclerosis by decoying the transcription factor Foxp1 (forkhead box transcription factor 1) away from target gene promoters, thereby activating NLRP3 inflammasome signaling in vascular endothelium 2. This mechanism is independent of the miR-181a1/b1 cluster it hosts 2.

• Expression is significantly elevated in atherosclerotic lesions in both human and mouse models, with abundant expression specifically in endothelial cells 2
• Genetic deletion of MIR181A1HG reduces atherosclerosis by decreasing NLRP3 inflammasome signaling, endothelial cell activation, monocyte infiltration, and atherosclerotic lesion formation 2
• Transcriptional activation occurs via NF-κB/p65-dependent pathway in response to inflammatory stimuli 2

Cancer Metastasis and Tumor Microenvironment

MIR181A1HG promotes colorectal liver metastasis by being packaged into extracellular vesicles (EVs) and delivered to hepatic stellate cells, where it functions as a competing endogenous RNA (ceRNA) 3.

• MIR181A1HG in EVs sponges miR-373-3p to activate hepatic stellate cells via the TGFβRII/Smad2/3 signaling pathway 3
• Activated stellate cells secrete CXCL12 chemokine, which remodels the extracellular matrix and recruits myeloid-derived suppressor cells to form premetastatic niches in the liver 3
• Expression is progressively upregulated from healthy controls to colorectal cancer to liver metastatic tissues, and is detectable in serum EVs 3
• HNRNPA2B1 mediates the packaging of MIR181A1HG into cancer cell-derived extracellular vesicles 3

Relationship to MicroRNA Cluster

MIR181A1HG serves as the host gene for miR-181a1 and miR-181b1, which themselves have distinct regulatory functions 2. The mir-181 family originated in urochordata and evolved through multiple duplications including two rounds of whole genome duplications and one round of segmental replication 4.

• MiR-181a regulates inflammatory responses by directly targeting the 3'-UTR of IL1a and down-regulating IL1a levels in monocytes and macrophages 5
• MiR-181a functions as an oncomir in gastric cancer by targeting the tumor suppressor gene ATM (ataxia-telangiectasia mutation), promoting proliferation and inhibiting apoptosis 6
• The mir-181 family participates in transcriptional and translational regulation and signaling transduction across multiple biological processes 4

Clinical Implications

MIR181A1HG represents a potential therapeutic target for vascular inflammatory disease states, as endothelial cell-specific overexpression promotes atherosclerosis while genetic deletion provides atheroprotection 2. The effects of MIR181A1HG overexpression can be reversed by pharmacological NLRP3 inhibition with MCC950 2.

MIR181A1HG in serum EVs may serve as a predictive biomarker for colorectal liver metastasis, given its progressive upregulation from healthy to metastatic states 3.

Important Caveats

• MIR181A1HG functions independently of its hosted microRNAs (miR-181a1/b1) in regulating vascular inflammation, indicating distinct mechanistic pathways 2
• Genetic deletion in myeloid cells does not alter atherosclerosis progression, indicating the primary pathogenic role is mediated through endothelial cells rather than immune cells 2
• Single-cell RNA sequencing reveals that MIR181A1HG deficiency reduces the proportion of immune cells and enriches anti-inflammatory pathways specifically in endothelial cell clusters within atherosclerotic lesions 2