In the genome of eukaryotes, transposable and repetitive elements (TREs) account for a large proportion with many TREs inserted into the intron region of protein-coding genes. For example, in human and mouse genomes, 60% of the transposable elements (TEs) are located in the intron, and more than 10% of the intron contains more than 1 kb TE insertion.
These intronic TREs are often heterochromatic with the enrichment of DNA methylation and repressive histone modifications. In general, heterochromatin has an inhibitory effect on the expression of adjacent genes. Interestingly, the insertion of heterochromatic elements such as TRE in intron does not affect the normal expression of the gene, and the underlying mechanism remains unclear.
A research team led by Dr. ZHU Jiankang and Dr. DUAN Chengguo at Shanghai Institute of Plant Physiology and Ecology of Chinese Academy of Sciences has been focusing on dissecting the interaction between epigenetic silencing and RNA processing. They recently identified the potential interacting proteins of ANTI-SILENCING 1 (ASI1) using a biochemical method, including ASI1-immunoprecipitated protein 1 (AIPP1), AIPP2, AIPP3 and AIPP4 (CPL2). The study was published online in PNAS.
In previous studies, researchers have found that the chromatin regulator ASI1 and the histone H3K9me-binding protein EDM2 (ENHANCED DOWNY MILDEW 2) were able to interact with the heterochromatin elements in the intron to control the proper RNA processing of associated genes by promoting the distal polyadenylation, thereby promoting the production of full-length transcripts (Wang et al., 2013, PNAS; Lei et al., 2014, PNAS). Although ASI1 and EDM2 function similarly in intronic heterochromatin-mediated RNA processing, the relationship between these two factors has been poorly understood.
This study revealed that AIPP1 can act as a "bridge" protein to mediate the intracellular connection of ASI1 and EDM2 and form a protein complex: AAE complex (ASI1-AIPP1-EDM2). Similar to ASI1 and EDM2, AIPP1 dysfunction was found to lead to increased accumulations of short transcript for a large number of intronic TRE-containing genes, but a lack of functional full-length transcripts, including the histone H3K9me2 demethylase IBM1-encoding gene. IBM1 is able to inhibit CHG hypermethylation of protein-encoding genes, therefore the gene body CHG hypermethylation is observed in thousands of protein-coding genes in the aipp1 mutant.
More interestingly, PHD domain-containing AIPP2 protein, BAH domain-containing AIPP3 protein and CPL2 can form the other complex, and its role in RNA processing is significantly different from that of the AAE complex, suggesting more complex regulatory mechanisms for heterochromatin-mediated RNA processing pathway.
The results are of great significance to understand the interaction between heterochromatin silencing and RNA processing mechanism in epigenetic modification of higher eukaryotes.
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