The long noncoding RNA Malat1: Its physiological and pathophysiological functions

Abstract

Recent studies suggest that in humans, DNA sequences responsible for protein coding regions comprise only 2% of the total genome. The rest of the transcripts result in RNA transcripts without protein-coding ability, including long noncoding RNAs (lncRNAs). Different from most members in the lncRNA family, the metastasis-associated lung adenocarcinoma transcript 1 (Malat1) is abundantly expressed and evolutionarily conserved throughout various mammalian species. Malat1 is one of the first identified lncRNAs associated with human disease, and cumulative studies have indicated that Malat1 plays critical roles in the development and progression of various cancers. Malat1 is also actively involved in various physiologic processes, including alternative splicing, epigenetic modification of gene expression, synapse formation, and myogenesis. Furthermore, extensive evidences show that Malat1 plays pivotal roles in multiple pathological conditions as well. In this review, we will summarize latest findings related to the physiologic and pathophysiological processes of Malat1 and discuss its therapeutic potentials.

Keywords: Long noncoding RNA; Malat1; cancer; cardiovascular disease; neurologic disorder; stroke.

Figure 1.

Biogenesis of Malat1. The 3′ end of Malat1 primary transcript is generated by tRNA biogenesis factors, yielding two RNAs: a nuclear-retained long noncoding Malat1 RNA and a tRNA-like small RNA (mascRNA). RNaseP recognizes a specific secondary structure near the 3′-end of Malat1 transcript and generates the mature 3′ end of Malat1 and the 5′ end of mascRNA. The tRNA-like small RNA is then cleaved by RNaseZ, subjected to CCA addition and exported to the cytoplasm. The mature Malat1 transcript localizes to nuclear speckles and its 3′ end is protected by a triple helical structure.

Figure 2.

Pathological functions of Malat1. Dysregulation of Malat1 contributes to various human diseases through different mechanisms. Cancer: Upregulation of Malat1 expression has been observed in many types of cancer. Malat1 drives tumor progression through regulating tumor cell proliferation, migration, metastasis and blood-tumor-barrier permeability. Myocardial infarction: Malat1 is upregulated in MI patients and inhibits miR-145 expression. Diabetic mellitus: high glucose levels induce the expression of Malat1, serum amyloid antigen 3 (SAA3), TNFα and IL-6 in endothelial cells. Diabetic retinopathy: Malat1 is increased in diabetic retinopathy and affects endothelial cell function. Endothelial function: Malat1 is induced by hypoxic stress and contributes to proliferation and migration of endothelial cells and a reduction in apoptosis. Ischemic stroke: Malat1 plays protective roles in ischemic stroke through regulating pro-apoptotic Bim and pro-inflammatory E-selectin. Parkinson disease: Malat1 is upregulated in PD mice and increases the stability of α-Synuclein.