LINC01431 Promotes Histone H4R3 Methylation to Impede HBV Covalently Closed Circular DNA Transcription by Stabilizing PRMT1

Abstract

Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV), which interacts with both host and viral proteins to form minichromosome in the nucleus and is resistant to antiviral agents. Identification of host factors involved in cccDNA transcriptional regulation is expected to prove a new venue for HBV therapy. Recent evidence suggests the involvement of long noncoding RNAs (lncRNAs) in mediating the interaction of host factors with various viruses, however, lncRNAs that HBV targets and represses cccDNA transcription have not been fully elucidated. Here, the authors identified LINC01431 as a novel host restriction factor for HBV transcription. Mechanically, LINC01431 competitively bound with type I protein arginine methyltransferase (PRMT1) to block the HBx-mediated PRMT1 ubiquitination and degradation. Consequently, LINC01431 increased the occupancy of PRMT1 on cccDNA, leading to enhanced H4R3me2a modification and reduced acetylation of cccDNA-bound histones, thereby repressing cccDNA transcription. In turn, to facilitate viral replication, HBV transcriptionally repressed LINC01431 expression by HBx-mediated repression of transcription factor Zinc fingers and homeoboxes 2 (ZHX2). Collectively, the study demonstrates LINC01431 as a novel epigenetic regulator of cccDNA minichromosome and highlights a feedback loop of HBx-LINC01431-PRMT1 in HBV replication, which provides potential therapeutic targets for HBV treatment.

Lnc_000048 Promotes Histone H3K4 Methylation of MAP2K2 to Reduce Plaque Stability by Recruiting KDM1A in Carotid Atherosclerosis

“…Subcellular localization of lncRNAs can indicate their possible mode of action in cells such as competing endogenous RNA (ceRNA) [36]. LncRNAs can induce epigenetic modifications and regulate the transcription of target genes by co-locating with proteins in the nucleus [37]. Ren et al proposed that lncRNA PLACT1 and hnRNPA1 co-localized in the nucleus and then induced an increase of H3K27, which reduces the transcription level of IκBα [38].…”

Co-Transcriptional Regulation of HBV Replication: RNA Quality Also Matters

“…Conversely, trimethylation of H3K9 or H3K27 catalyzed by SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) and the polycomb repressive complex 2 (PRC2), respectively, are associated with transcriptional silencing of cccDNA [ 54 , 60 , 61 ]. Similarly, methylation of the arginine residue of histone H4 (H4R3me) catalyzed by PRMTs is associated with the repression of cccDNA transcriptional activity [ 53 , 62 ]. These data thus highlight a tight epigenetic regulation of cccDNA activity.…”

“… Regulators of HBV cccDNA transcription. Examples of host or viral factors activating (green) or silencing (red) cccDNA transcriptional activity associated with an active (green nucleosomes) or a silent (red nucleosomes) chromatin [ 37 , 38 , 39 , 40 , 43 , 47 , 48 , 49 , 50 , 52 , 53 , 54 , 56 , 57 , 58 , 59 , 60 , 62 , 63 , 65 , 66 , 67 , 68 , 70 , 74 , 75 , 76 , 77 ]. The image was created using Biorender.com.…”

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

“…PRMTs catalyze the methylation on histone tail arginine that is directly involved in the control of the transcription of target genes, either by compacting or decompacting the chromatin for the transcriptional repression or activation, respectively ( Figure 1 ) [ 7 ]. Some of these histone arginine methylations contribute to an activation of the transcription of target genes, which include the arginine 3 of histone 4 asymmetrical demethylation (H4R3me2a) by PRMT1 and PRMT3 [ 8 , 9 ], the H3R17me2a mark catalyzed by CARM1 [ 10 , 11 ], and the H3R2 symmetrical demethylation (H3R2me2s) by PRMT5 [ 12 ]. The arginine methylation of histones can also be associated with a repressive chromatin state, as shown with the H4R3 and H2AR3 monomethylation by PRMT7 [ 13 ], PRMT5 H3R8me2s [ 14 ], and PRMT6 H3R2me2a marks [ 15 ].…”