Japanese researchers have been able to visualize how a protein is able to silence “jumping genes” that can mutate to cause genetic conditions.
The findings show how a chromatin remodeler called Decreased in DNA Methylation (DDM)1 opens access to these jumping genes, otherwise known as transposons, deep within DNA-protein complexes.
DDM1 thereby makes the transposons more accessible so that chemical marks can be deposited that prevent their transcription.
The findings come from a small plant in the mustard family called Arabidopsis thaliana, or Thale cress. But researcher Akihisa Osakabe, PhD, from the University of Tokyo, noted that a human version of DDM1 calls HELLS works similarly.
“In the long term, such discoveries could lead to new treatments for genetic diseases in humans caused by similar genes,” he suggested. The research is published in the journal Nature Communications.
The DDM1 protein maintains suppressing chemical marks against jumping genes, but it has not been clear how it is able to access these transposons.
The team used cryo-electron microscopy (EM), which images at near-atomic scale, to discover how DDM1 opens up the structure of the H2A.W nucleosome, a section of DNA wrapped around proteins.
DDM1 enabled access to the “jumping gene” transposable elements, which are DNA sequences that can hop from one area of the genome to another.
Transposons are tucked deep within nucleosomes, making it difficult for the cell to deposit chemical marks that can suppress their transcription.
The cryo-EM structures of Arabidopsis nucleosomes revealed how they complex with the chromatin remodeler DDM1 and offered insights into how DDM1 promoted the access of chromatin writers to heterochromatin.
The images displayed the exact positions where DDM1 bound to nucleosomal DNA, at the SHL-2 and SHL+6 positions.
Crosslinking mass spectrometry and biochemical analyses suggested that DDM1 contacted the H2A.W-specific C-terminal tail and increased the flexibility of the entry/exit DNA regions in the H2A.W nucleosome.
The findings indicated that DDM1 binding changed the structure of the H2A.W nucleosome, although the researchers note they did not detect a direct interaction between H2A.W and DDM1 in the cryo-EM structure of the DDM1-H2A.W nucleosome complex.
They therefore suggest that some disordered regions that were not detected by cryo-EM contribute to the flexible entry/exit DNA ends of the DDM1-bound H2A.W nucleosome.
“Jumping genes are fascinating, because they can cause significant changes in the genome, both good and bad” said Osakabe.
“Studying how proteins like DDM1 manage these genes helps us understand the basic mechanisms of life and can have important practical applications.”
