Chromatin is the physiological template of our
genetic information, the
DNA double helix. The basic subunits of
chromatin, the
histone proteins, function in the packaging of the
DNA double helix and in controlling
gene expression through a variety of histone modifications. When Jenuwein started his
chromatin work in late 1993, no enzymes for histone modifications were known. He and his team cloned and characterized mammalian orthologs of dominant
Drosophila PEV modifier factors containing the evolutionarily conserved
SET domain, originally identified by the laboratory of Gunter Reuter. The
SET domain is present in Su(var)3–9,
Enhancer of zeste and
Trithorax proteins, all of which had been implicated in
epigenetic regulation without evidence of enzymatic activity. Overexpression of human
SUV39H1 modulated the distribution of
histone H3 phosphorylation during the
cell cycle in a
SET domain dependent manner. This insight, together with refined bioinformatic interrogation revealing a distant relationship of the
SET domain with plant methyltransferases, suggested the critical experiment: to test recombinant
SUV39H1 for KMT activity on
histone substrates. This experiment revealed robust catalytic activity of the
SET domain of recombinant
SUV39H1 to methylate
histone H3 in vitro An important follow-up discovery was to show that SUV39H1-mediated H3K9 methylation generates a binding site for the
chromodomain of
heterochromatin protein 1 (HP1). Together, these landmark findings established a biochemical pathway for the definition of
heterochromatin and characterized Suv39h-dependent H3K9me3 as a central epigenetic modification for the repression of transcriptional activity. The in vivo function of the Suv39h KMT was demonstrated by the analysis of Suv39h double-null mice, which display
chromosome segregation defects and develop
leukemia. Together with
Boehringer Ingelheim, he identified the first small molecule inhibitor for KMT enzymes via screening of a chemical library. During the following years, Jenuwein then addressed the function of
heterochromatin towards
transcriptional regulation and
genomic organization, with a particular focus on the analysis of the non-coding genome. An initial map of the mouse
epigenome was established by a cluster analysis of repressive histone modifications across repeat sequences and provided an important framework well ahead of the deep-sequencing advances in the profiling of
epigenomes. Genome-wide maps for Suv39h-dependent
H3K9me3 marks and Hiseq RNA sequencing revealed a novel role for the Suv39h KMT in the
silencing of repeat elements (e.g. LINE and ERV
retrotransposons) in mouse
embryonic stem cells. The demonstration that the pericentric
major satellite repeats have embedded
transcription factor (TF) binding sites that are relevant for TF-mediated recruitment of Suv39h enzymes has provided a general targeting mechanism for the formation of
heterochromatin. Most recent work has identified that repeat RNA transcripts from the
major satellite repeats largely remain
chromatin associated and form an RNA-
nucleosome scaffold that is supported by RNA:DNA hybrids. == Significance and impact ==