Oligodendroglioma cells synthesize the differentiation-specific linker histone H1˚ and release it into the extracellular environment through shed vesicles

Abstract

Chromatin remodelling can be involved in some of the epigenetic modifications found in tumor cells. One of the mechanisms at the basis of chromatin dynamics is likely to be synthesis and incorporation of replacement histone variants, such as the H1˚ linker histone. Regulation of the expression of this protein can thus be critical in tumorigenesis. In developing brain, H1˚ expression is mainly regulated at the post-transcriptional level and RNA-binding proteins (RBPs) are involved. In the past, attention mainly focused on the whole brain or isolated neurons and little information is available on H1˚ expression in other brain cells. Even less is known relating to tumor glial cells. In this study we report that, like in maturing brain and isolated neurons, H1˚ synthesis sharply increases in differentiating astrocytes growing in a serum-free medium, while the corresponding mRNA decreases. Unexpectedly, in tumor glial cells both H1˚ RNA and protein are highly expressed, in spite of the fact that H1˚ is considered a differentiation-specific histone variant. Persistence of H1˚ mRNA in oligodendroglioma cells is accompanied by high levels of H1˚ RNA-binding activities which seem to be present, at least in part, also in actively proliferating, but not in differentiating, astrocytes. Finally, we report that oligodendroglioma cells, but not astrocytes, release H1˚ protein into the culture medium by shedding extracellular vesicles. These findings suggest that deregulation of H1˚ histone expression can be linked to tumorigenesis.