Researchers identify mechanism that silences “parasitic” DNA-elements in pluripotent stem cells

Every eukaryotic organism (a cell with clearly defined nucleus) contains the so-called transposons, which are abundant DNA-elements. This consequence can be attributed to their potential to skip and multiply inside the host genome.

Simon Elsässer. Photo: Markus Marcetic © Knut and Alice Wallenbergs Stiftelse / Kungl. The Academy of Sciences.

Their activity represents a threat to the integrity of the host genome and thus the host cell engages a number of protective mechanisms to silence the expression of transposons.”

Simon Elsässer, Researcher, Department of Medical Biochemistry and Biophysics, Karolinska Institutet

It is a well-known fact that a few of these mechanisms fail in cancer cells and even in aging cells, resulting in a mobilization of transposons with consequences that are largely unknown.

Histones are essentially proteins that package the genome in the eukaryotic nucleus. They are crucial to the most underlying line of defense to transposons. When histones form a highly compacted array, so-called heterochromatin, they make the related DNA sequence inert to being read and expressed.

Heterochromatin is typically defined by characteristic alterations to DNA and histone proteins, like DNA CpG methylation and histone H3 K9 trimethylation.

The team of Simon Elsässer examined endogenous retroviral elements (ERVs)—an abundant and specifically active family of transposable elements in the mouse genome—which are actually remnants of viruses that were once active.

Peculiarly, while the team identified all the characteristics of heterochromatin to be used in the silencing mechanism, ERV chromatin was extremely enriched in a histone variant called histone H3.3, which has always been linked with the genome’s active regions.

The researchers, who followed up on this remark, could explain a sudden mechanism involving a steady loss of “old” histones and replenishment with newly produced histones H3.3 molecules.

Through genetic manipulation, the researchers were able to figure out a mechanism that describes this dynamic process—the ATP-dependent chromatin remodeler Smarcad1 removes histones inside the heterochromatin, thus generating gaps in the chromatin fiber that could provide access to parts of the ERV gene.

The histone chaperone DAXX follows suit and locks these gaps by enabling the reassembly of nucleosomes with histone variant H3.3.

The concerted process of eviction of one and deposition of another histone is so smooth and efficient that it leaves no apparent trace of accessible DNA. Without a close look at the dynamics of histones within the chromatin fiber, we would have never noticed the phenomenon.”

Simon Elsässer, Researcher, Department of Medical Biochemistry and Biophysics, Karolinska Institutet

The outcome is mysterious because active remodeling and the eviction of nucleosomes are anticipated to offset a compacted structure of chromatin, which is inert to transcriptional activation.  But according to the researchers, dynamic heterochromatin is an adaption of an ever-present  silencing mechanism to the particular needs of a pluripotent chromatin state.

The extremely transient opening of heterochromatin may enable sequence-specific co-repressors to identify the sequence of their target DNA inside the transposable element, consequently recruiting more repressive factors to propagate and increase the silent state.

The researchers have respectively observed driver mutations and dysregulation of DAXX, H3.3 and Smarcad1 in numerous types of cancer. The latest research provides new indications that reactivation of silenced transposable elements may contribute to their tumorigenesis.