Human Endogenous Retroviruses (HERVs) are ancestral retroviral sequences that integrated into the human genome and their expression are tightly controlled by epigenetics. Intriguingly, dysregulation of HERVs is associated with many diseases including cancer and autoimmune diseases. Double-stranded RNA (dsRNA) generated from the bidirectional transcription of HERVs can trigger the viral mimicry pathway and is an emerging target for cancer immunotherapy. Viral proteins derived from HERVs also have the capacity to provoke immune responses through molecular mimicry. Hence, it is hypothesized that epigenetic and transcriptional alteration of HERVs potentially leads to the development of autoimmune diseases. However, the precise mechanisms of how HERVs are repressed and contribute to...[ Read more ]

Human Endogenous Retroviruses (HERVs) are ancestral retroviral sequences that integrated into the human genome and their expression are tightly controlled by epigenetics. Intriguingly, dysregulation of HERVs is associated with many diseases including cancer and autoimmune diseases. Double-stranded RNA (dsRNA) generated from the bidirectional transcription of HERVs can trigger the viral mimicry pathway and is an emerging target for cancer immunotherapy. Viral proteins derived from HERVs also have the capacity to provoke immune responses through molecular mimicry. Hence, it is hypothesized that epigenetic and transcriptional alteration of HERVs potentially leads to the development of autoimmune diseases. However, the precise mechanisms of how HERVs are repressed and contribute to autoimmunity still remain elusive.

This study is divided into three objectives: 1. Screen for novel HERV regulators using cancer cell lines to understand the underlying HERVs repression mechanisms. 2. Examine the transcriptome and epigenetic profiles of Systemic Lupus Erythematosus (SLE) patients to investigate the expression change of HERVs. 3. Determine the prevalence of Transposable Elements (TEs) dysregulation in Chronic Inflammation Diseases (CID) through analyzing cohort’s epigenome and transcriptome. Firstly, utilizing a genome-wide CRISPR/Cas9 knock-out approach, I have identified candidate epigenetic repressors of HERVs. Furthermore, I have examined the genome-wide chromatin states and transcriptomic changes in SLE patients and conducted pilot analyses with CID cohort’s transcriptomic data, showing that TEs are differentially expressed in SLE and other CID, concomitant with increased expression of immune-response genes. These findings may improve our understanding of the molecular mechanisms of HERVs regulation and its role in immune disease pathogenesis.