A new function for histone variants in the tissue-specific regulation of pre-mRNA splicing (#111)
Chromatin is a highly dynamic and hierarchical structure. Its main function is to package cellular genome in a way that will allow the regulation of gene expression and silencing. The basic subunit of chromatin is a nucleosome, which is comprised of 8 histone proteins and the DNA that is wrapped around the histone core. In order to understand how chromatin regulates genome function, we study histone variants, which can be viewed as natural histone mutants, and provide an excellent platform to investigate alterations in the structure and function of chromatin in the presence of such variants.
Recently, we have identified a unique tissue-specific mouse H2A histone variant, H2A.Lap1 (Lack of Acidic Patch), which is expressed exclusively in the testis and in the brain. We have shown that this variant is a novel component of the Transcription Start Site (TSS) of active genes expressed during specific stages of spermatogenesis1 .
Here, we report a new function for H2A.Lap1 in the brain, where the H2A.Lap1-containing nucleosomes were significantly enriched at the exon/intron boundary of active genes (the same was also confirmed in the testis), implying a role in pre-mRNA splicing. Further, our analysis revealed that H2A.Lap1 is not just marking the exon/intron boundaries in the testis and the brain, but also actively interacts with the pre-mRNA splicing machinery. Finally, in addition to being chromatin-bound, we have shown that H2A.Lap1 is transiently localised within nuclear speckles, chromatin-depleted sites of assembly and maintenance of the machinery involved in both splicing and transcription. We, therefore, propose that H2A.Lap1 represents a novel epigenetic mark that defines exon/intron boundaries and, simultaneously, recruits splicing factors via direct interaction with RNA-splicing machinery.
- Soboleva et. al. A unique H2A histone variant occupies the transcriptional start site of active genes. Nature structural & molecular biology. 2012 Jan;19(1):25-30.