Chinese Medical Journal study highlights transposable elements' role in health and disease

Transposable elements (TEs), long regarded as genomic "junk," are now recognized as pivotal regulators of gene expression, genome structure, and disease development. Comprising nearly 50% of the human genome, TEs include retrotransposons such as LINE-1 (L1), Alu, SVA, and endogenous retroviruses (ERVs), as well as DNA transposons. While most DNA transposons are now inactive, retrotransposons remain active in certain contexts, impacting genome stability and regulatory functions.

TEs are categorized into Class I (retrotransposons) and Class II (DNA transposons) based on their mobilization mechanisms. Class I elements transpose via an RNA intermediate and include LTR elements like HERVs and non-LTRs like LINE-1 and SINEs (e.g., Alu and SVA). L1 is the only autonomous active TE in humans, encoding proteins ORF1p and ORF2p necessary for retrotransposition. Alu and SVA rely on L1 machinery for mobilization. While tightly silenced in most somatic cells, TEs are transiently activated during critical developmental stages, particularly in embryogenesis.

Now, a review authored by researchers from China, led by Dr. Nian Liu from the School of Life Sciences, Tsinghua University, details a multilayered regulatory system that silences TEs, including DNA methylation, histone modifications, chromatin remodeling, RNA interference, and RNA-binding proteins. For example, the KRAB-ZFP/KAP1 complex recruits SETDB1 to deposit repressive H3K9me3 marks at young L1s and ERVs. Small RNAs (e.g., piRNAs and siRNAs) degrade TE-derived transcripts, and RNA modifications like m6A or m5C regulate TE RNA fate. Despite this, some TEs escape repression through promoter mutations or 5' UTR deletions, allowing persistent expression. The review was published in Volume 138, Issue 18, of the Chinese Medical Journal on September 20, 2025.

Dr. Nian Liu explains, "Understanding the complex regulation of transposable elements provides crucial insights into their dual roles in maintaining genomic stability and contributing to disease." She adds, "Our findings open new avenues for targeted therapies that modulate TE activity, potentially transforming treatment approaches for a range of diseases."

Functionally, TEs influence gene regulation through exon insertion, enhancer activity, and alternative splicing. L1s and ERVs contribute to the formation of chromatin compartments and topologically associating domains, shaping genome architecture. As enhancers, L1s and HERVH regulate transcription in pluripotent stem cells and during zygotic genome activation (ZGA). L1 RNAs also act in trans as scaffolds to modulate chromatin accessibility and gene expression.

Physiologically, TEs play critical roles in embryogenesis, particularly during ZGA and placental development. L1s and HERVs act as stage-specific enhancers or alternative promoters, with MER50 and RLTR13 contributing to placental gene regulation. In the brain, L1 and Alu influence neural development, synaptic plasticity, and neurogenesis. Aberrant TE activation has been implicated in neurological disorders like schizophrenia, autism spectrum disorder, Rett syndrome, amyotrophic lateral sclerosis, and Alzheimer’s disease through insertional mutagenesis, inflammation, and genomic instability.

In immunity, TEs act as innate immune triggers through dsRNA or cDNA recognition by sensors like RIG-I, cGAS, and TLRs. ERVs and L1s also serve as IFN-inducible enhancers and modulate adaptive immune responses, including T cell function. Their dysregulation can contribute to autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis by promoting chronic inflammation and immune dysfunction.

Aging is another context where TEs play a detrimental role. With age, epigenetic silencing of TEs erodes, leading to their activation. L1 expression contributes to DNA damage and chronic inflammation ("inflammaging"), and reverse transcriptase inhibitors (e.g., 3TC) are being explored to suppress this activity.

In cancer, TEs are reactivated in over 50% tumors, particularly colorectal and esophageal cancers. L1 insertions can disrupt tumor suppressor genes like APC and PTEN. TE reactivation also leads to copy number variation and genome instability. Furthermore, TE-derived transcripts and peptides can generate tumor-specific neoantigens, presenting opportunities for cancer immunotherapy, including vaccines and CAR-T strategies. Epigenetic drugs that unmask TE antigens (e.g., DNMT and HDAC inhibitors) enhance tumor immunogenicity and response to checkpoint blockade.

In diagnostics and therapy, TEs show promise as biomarkers. Their expression can be detected in circulating DNA or cerebrospinal fluid, aiding cancer and neurodegenerative disease diagnosis. Therapeutically, antisense oligonucleotides and reverse transcriptase inhibitors have shown potential in preclinical models. Advances in single-cell and long-read sequencing now allow precise mapping of TE activity, revealing cell-specific patterns and enabling more accurate diagnostics and treatment stratification. Looking forward, machine learning is emerging as a tool for predicting immunogenic TE-derived epitopes. Integration of TE profiling with epigenomic and transcriptomic data will improve our understanding of TE regulation and function, paving the way for personalized therapies targeting disease-specific TE signatures.