Group Leader

Prof. Dr. Thomas Jenuwein
Prof. Dr. Thomas Jenuwein
Senior Group Leader & Director
Phone:+49 761 5108-785

Lab Thomas Jenuwein

Assistant: Marcela Mare Phone: +49 761 5108 574 Email: mare@ie-freiburg.mpg.de

Laboratory Thomas Jenuwein

How to break heterochromatin

Although the Suv39h methyltransferases (KMTs) are known to ensure pericentric H3K9me3 methylation, the mechanisms that initiate and maintain mammalian heterochromatin organization remain elusive. While Suv39h dn cells display dispersed H3K9me3, H3K9me1 accumulates at pericentric regions, indicating the action of a specific H3K9me1 KMT.

Figure 2: Impaired Prdm3/Prdm16 function disintegrates heterochromatic foci. DNA-FISH for major satellite repeats in wild-type iMEF cells upon control and Prdm3/Prdm16 double knock-down. DNA is shown in blue and DNA FISH signals in green. Zoom Image

Figure 2: Impaired Prdm3/Prdm16 function disintegrates heterochromatic foci. DNA-FISH for major satellite repeats in wild-type iMEF cells upon control and Prdm3/Prdm16 double knock-down. DNA is shown in blue and DNA FISH signals in green.

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We developed a biochemical assay and used in vivo analyses in murine embryonic fibroblast cells (MEFs) to identify Prdm3 and Prdm16 as redundant H3K9me1-specific KMTs that direct cytoplasmic H3K9me1 methylation (Pinheiro et al., 2012). The H3K9me1 is converted in the nucleus to H3K9me3 by the Suv39h enzymes to reinforce heterochromatin. Simultaneous depletion of Prdm3 and Prdm16 abrogates H3K9me1 methylation, prevents Suv39h-dependent H3K9me3 and derepresses major satellite transcription. Most strikingly, DNA-FISH and electron microscopy reveal that combined impairment of Prdm3 and Prdm16 results in disintegration of heterochromatic foci and disruption of the nuclear lamina (see Figure). Our data identify Prdm3 and Prdm16 as H3K9me1 methyltransferases and expose a functional framework in which anchoring to the nuclear periphery helps maintain the integrity of mammalian heterochromatin.

We will now focus on the detailed molecular mechanism, by which these enzymes exert their function. In particular, we are interested in exploring a potential deposition related mechanism for H3K9me1 and signalling pathways that may regulate the enzymatic activity of Prdm3 and Prdm16.

 
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