Younggun Lee

HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators

Significance Epigenetic dysregulation by oncoviral protein plays a key role in tumor development. DNA methylome analysis of hepatitis B virus X (HBx)-induced hepatocellular carcinoma (HCC) revealed drastic changes in host epigenome, but in an unconventional way: intragenic CpG islands (CGIs) were dramatically demethylated. We showed methylated intragenic CGIs as previously unidentified regulatory elements associated with active expression. The methylated CGIs are marked with distinct epigenetic signatures and require DNA methyltransferase (DNMT) 3L complex for their high methylation levels. By directly suppressing Dnmt3L and Dnmt3a promoters, HBx induces hypomethylation of the intragenic CGIs and downregulation of the associated developmental regulators. We provide previously unreported functional identification of intragenic CGIs that may enhance our understanding of epigenetic regulation and a new epigenetic role for HBx in promoting HCC development. Epigenetic alterations caused by viral oncoproteins are strong initiation factors for cancer development, but their mechanisms are largely unknown. To identify the epigenetic effects of viral hepatitis B virus X (HBx) that lead to hepatocellular carcinoma (HCC), we profiled the DNA methylomes of normal and HBx transgenic mouse liver. Intriguingly, severe hypomethylation of intragenic CpG islands (CGIs) was observed in HBx liver before the full development of HCC. Normally, these CGIs were highly methylated (mCGIs) by the DNMT3L complex and marked with epigenetic signatures associated with active expression, such as H3K36me3. Hypomethylation of mCGI was caused by the downregulation of Dnmt3L and Dnmt3a due to HBx bound to their promoters, along with HDAC1. These events lead to the downregulation of many developmental regulators that could facilitate tumorigenesis. Here we provide an intriguing epigenetic regulation mediated by mCGI that is required for cell differentiation and describe a previously unidentified epigenetic role for HBx in promoting HCC development.

Genome-wide methylation profiling of ADPKD identified epigenetically regulated genes associated with renal cyst development

Autosomal dominant polycystic kidney disease (ADPKD) is a common human genetic disease characterized by the formation of multiple fluid-filled cysts in bilateral kidneys. Although mutations in polycystic kidney disease 1 (PKD1) are predominantly responsible for ADPKD, the focal and sporadic property of individual cystogenesis suggests another molecular mechanism such as epigenetic alterations. To determine the epigenomic alterations in ADPKD and their functional relevance, ADPKD and non-ADPKD individuals were analyzed by unbiased methylation profiling genome-wide and compared with their expression data. Intriguingly, PKD1 and other genes related to ion transport and cell adhesion were hypermethylated in gene-body regions, and their expressions were downregulated in ADPKD, implicating epigenetic silencing as the key mechanism underlying cystogenesis. Especially, in patients with ADPKD, PKD1 was hypermethylated in gene-body region and it was associated with recruitment of methyl-CpG-binding domain 2 proteins. Moreover, treatment with DNA methylation inhibitors retarded cyst formation of Madin-Darby Canine Kidney cells, accompanied with the upregulation of Pkd1 expression. These results are consistent with previous studies that knock-down of PKD1 was sufficient for cystogenesis. Therefore, our results reveal a critical role for hypermethylation of PKD1 and cystogenesis-related regulatory genes in cyst development, suggesting epigenetic therapy as a potential treatment for ADPKD.

Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease.

Rapid eye movement sleep behaviour disorder (RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cpRBD) in patients with Parkinsons disease (PD) is associated with a specific pattern of striatal dopamine depletion.

Henoch-Schönlein Purpura Presenting as Mononeuritis Multiplex

Dear Editor, Mononeuritis multiplex (MM) is a syndrome of the peripheral nervous system (PNS) involving progressive multifocal peripheral nerve lesions. Its distribution is typically asymmetric, and the course of the disease varies with the underlying etiology. MM is associated with several medical conditions, including vasculitis, immune-mediated diseases, diabetes, infections, neoplasms, infiltrative diseases, and drugs. Henoch-Schönlein purpura (HSP) is an IgA-mediated small-vessel vasculitis, and also a rare cause of MM.1 The prevalence of HSP is lower in adults than in children, and no cases of MM with HSP in Korea have been reported previously. Here we report a case of MM with HSP in a Korean patient. A 57-year-old female patient visited the emergency room due to weakness of her right ankle and right hand. She had been diagnosed with rheumatoid arthritis (RA) 10 years previously due to multiple arthralgia. Her RA was well controlled with medication, and she had no arthralgia at the present visit. One day before her presentation she had experienced shock-like pain that developed along her right upper arm and in her right ankle. A neurologic examination revealed weakness of wrist flexion, thumb abduction, and ankle dorsiflexion, and hypesthesia of the right finger tips and foot dorsum. Purpuric skin lesions had developed on both feet 1 year before the current presentation, and the patient reported diffuse nonspecific abdominal pain (Supplementary Fig. 1 in the online-only Data Supplement). She had undergone a skin biopsy 1 month previously, which revealed leukocytoclastic vasculitis and IgA deposition within the purpuric lesion. The patient was diagnosed with HSP based on IgA vasculitis, purpuric skin lesions, and diffuse abdominal pain. A nerve conduction study revealed multifocal axonal neuropathy (Table 1), leading to a diagnosis of MM. Laboratory tests revealed mild leukocytosis, elevated C-reactive protein and increased erythrocyte sedimentation rate (60.3 mg/L and 45 mm/hr, respectively). The findings of serologic tests were negative for antineutrophil cytoplasmic antibody, anti-SS-A antibody, anti-SS-B antibody, antinuclear ribonucleoprotein antibody, anti-Smith antibody, antihistone antibody, anti-double-stranded DNA antibody, cold agglutinin, and cryoglobulin. She was positive for antinuclear antibody at a titer of 1:640 and with a nucleolar pattern, and her serum rheumatoid factor was elevated (to >120 IU/L). The patient underwent methylprednisolone pulse therapy (1 g per day for 5 days) without significant complications, and she was maintained on low-dose oral steroid. Her ankle and wrist weakness had improved at the 1-year follow-up, but the sensory loss persisted. Among various etiologies, the most common cause of MM is vasculitic process, while HSP is rare.2 HSP is an immune complex vasculitis that predominantly affects small vessels, and is characterized by nonthrombocytopenic palpable purpura, abdominal involvement, arthralgia, and renal involvement. Its pathophysiology remains unclear, but IgA is thought to play an essential role.3 HSP mainly occurs in children and is uncommon in adults. FurtherMincheol Park Younggun Lee Young-Chul Choi

Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture

Background and Purpose The early diagnosis of LMNA-associated muscular dystrophy is important for preventing sudden arrest related to cardiac conduction block. However, diagnosing early-onset Emery-Dreifuss muscular dystrophy (EDMD) with later involvement of contracture and limb-girdle muscular dystrophy type 1B is often delayed due to heterogeneous clinical presentations. We aimed to determine the clinical features that contribute to a delayed diagnosis. Methods We reviewed four patients who were recently diagnosed with LMNA-associated muscular dystrophy by targeted exome sequencing and who were initially diagnosed with nonspecific or other types of muscular dystrophy. Results Certain clinical features such as delayed contracture involvement and calf hypertrophy were found to contribute to a delayed diagnosis. Muscle biopsies were not informative for the diagnosis in these patients. Conclusions Genetic testing of single or multiple genes is useful for confirming a diagnosis of LMNA-associated muscular dystrophy. Even EDMD patients could experience the later involvement of contracture, so clinicians should consider early genetic testing for patients with undiagnosed muscular dystrophy or laminopathy.

Volumetric analysis of the cerebellum in patients with progressive supranuclear palsy

Although early cerebellar symptoms are one of the exclusive criteria in the diagnosis of progressive supranuclear palsy (PSP), cerebellar involvement in PSP is evident both clinically and pathologically. However, structural analysis focusing on the cerebellum has not been previously studied in patients with PSP. We aimed to evaluate cerebellar involvement in PSP using a magnetic resonance imaging‐based segmental volumetric analysis.