Laboratory Thomas Jenuwein

Laboratory Thomas Jenuwein

Epigenetic control by histone lysine methylation

Research Overview

In the nuclei of almost all eukaryotic cells genomic DNA is compacted with histone and non-histone proteins in a dynamic polymer called chromatin. Several epigenetic mechanisms, such as nucleosome remodeling, histone modifications, DNA methylation and non-coding RNA function together to organize chromatin into accessible (euchromatic) and inaccessible (heterochromatic) domains. We discovered the Suv39h enzymes as the first histone lysine methyltransferases (KMT) and have shown that Suv39h-dependent histone H3 lysine 9 (H3K9me3) methylation is a central epigenetic modification for a repressed chromatin state at heterochromatic regions. 

Goal

The goal of our research is to dissect epigenetic gene regulation and to identify the underlying mechanisms that initiate and maintain heterochromatin in mammalian cells (Figure 1).

Molecular definition of mouse heterochromatin. The Figure highlights the basic mechanisms that build mammalian heterochromatin and shows a compacted array of nucleosomes that are enriched for DNA methylation (small Me hexagon), H3K9me3 histone methylation (big Me hexagon), binding of the Suv39h KMT and of heterochromatin protein 1 (HP1), and chromatin association of non-coding repeat RNA. Ongoing research projects are indicated by the yellow arrows.

Since heterochromatin has important functions in safe-guarding genome integrity, in silencing of endogenous retroviruses and in stabilizing gene expression programs, our research is of crucial importance for a better understanding of normal and perturbed development and for new insights to protect from disease progression.


Selected publications

1.
Duda K, Ching R, Jerabek L, Shukeir N, Erikson G, Engist B, Onishi-Seebacher M, Perrera V, Richter F, Mittler G, Fritz K, Helm M, Knuckles P, Bühler M, Jenuwein T (2021)
m6A RNA methylation of major satellite repeat transcripts facilitates chromatin association and RNA:DNA hybrid formation in mouse heterochromatin.
Nucleic Acids Research, in press.
2.
Walther M, Schrahn S, Krauss V, Lein S, Kessler J, Jenuwein T, Reuter G (2020)
Heterochromatin formation in Drosophila requires genome-wide histone deacetylation in cleavage chromatin before mid-blastula transition in early embryogenesis.
Chromosoma 129(1), 83-98.
3.
Velazquez Camacho O, Galan C, Swist-Rosowska K, Ching R, Gamalinda M, Karabiber F, De La Rosa-Velazquez I, Engist B, Koschorz B, Shukeir N, Onishi-Seebacher M, van de Nobelen S, Jenuwein T (2017)
Major satellite repeat RNA stabilize heterochromatin retention of Suv39h enzymes by RNA-nucleosome association and RNA:DNA hybrid formation.
eLife 6:e25293.
4.
Allis CD, Jenuwein T (2016)
The molecular hallmarks of epigenetic control.
Nature Review Genetics 17 (8), 487-500.
5.
Bulut-Karslioglu A, De La Rosa-Velázquez IA, Ramirez F, Barenboim M, Onishi-Seebacher M, Arand J, Galán C, Winter GE, Engist B, Gerle B, O'Sullivan RJ, Martens JH, Walter J, Manke T, Lachner M, Jenuwein T (2014)
Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells.
Molecular Cell 55, 277-290.

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