A novel code to interpret genetic information

Gene expression in multicellular eukaryotes is regulated by histones, proteins that directly associate with DNA. Among the five families of histones, the H2A family contains variants that specifically occupy either expressed genes, repressed genes, or transposons. The regulatory mechanisms that control their specific patterns of deposition of H2A variants remains largely unknown. We have identified that the chromatin remodeler DDM1 is responsible for the deposition of the variant H2A.W on transposons in flowering plants. This chromatin remodeler and its ortholog in mammals were identified twenty years ago for their impact on transposon silencing and DNA methylation but their mechanism of action had remained unclear. This proposal will use a new genomic approach to determine whether the deposition of H2A.W by DDM1 is directly responsible for transposon silencing. We will use a combination of genetic and biochemical approaches to identify regulatory partners of DDM1. As histones and their associated chromatin remodelers in animals evolved in parallel with those in plants, this research will impact our understanding of chromatin dynamics in all eukaryotes.

How eukaryotes evolved from simpler organisms is one of the most fundamental and least understood questions in biology. Compared with bacteria and archaea, eukaryotes' DNA is associated with a much larger diversity of modifiable protein complexes, forming the chromatin enclosed in the cell's nucleus. Chromatin protein complexes protect the integrity of the genetic code and carefully regulate access to its information to translate this code into proteins. Chromatin is thus an essential control center of each of our cells and we propose that the increased complexity of chromatin proteins in eukaryotes was a prerequisite for the evolution of multicellular life. We deployed interdisciplinary strategies based on complementary expertise in evolution, genetics, and structural biology to characterize the role of histone variants which are essential components of chromatin that diversified and neofunctionalized as complex eukaryotes evolved. We combined molecular phylogenomics and synthetic genetics, molecular biology and structural data to determine the function and evolutionary impact of the histone variant H2A.Z. This work establishes the central role of H2A.Z as a modulator of transcription. We propose that evolution of histone variants enabled a multi-layered interpretation of the genetic code to enable a temporal transcriptional program to support more complex development of complex multicellular plants and animals.