Kristian Helin: Role of epigenetic enzymes in stem cells and cancer

June 21, 2011; 3 PM

Auditorium: A1-05.01 (2-02)

Dyrlægevej 100, Frederiksberg

 

Prof. Kristian Helin Biocenter

Biotech Research & Innovation Centre and Centre for Epigenetics

University of Copenhagen

www.bric.ku.dk

A major goal of our research is to identify and characterize genes involved in the regulation of normal proliferation and differentiation that also contribute to the development of human disease. In addition to obtaining an understanding of basic mechanisms regulating development and differentiation, our aim is to identify and validate new targets for the development of anti-cancer therapy.

 

Consistent with an essential role of epigenetic enzymes in controlling cell-fate decisions, several of these are causally linked to the development of diseases, such as cancer and CNS-associated disorders. Histone methylation regulates chromatin structure and gene regulation. Histone methylation patterns define the state of chromatin and it is regulated by histone methyl transferases and demethylases. In the seminar I will present some of our recent data describing the functional characterization of some of these very exciting proteins - that also present strong candidate targets for the development of new targeted therapy.

 

DNA methylation of the 5-position of cytosine (mC) is believed to have essential roles in regulating gene expression, genome stability, and maintaining cellular identity. In current models for gene regulation, CpG methylation in promoters leads to stable gene silencing, whereas the function of intragenic methylation might, like trimethylation of H3 lysine 36 (H3K36me3), repress the initiation of intragenic transcription. Hence, demethylation of CpG-methylated promoters is believed to facilitate to a transcriptional state that is permissive for gene activation. Recently Tet1 was found to hydroxylate the methyl group of mC converting it to 5-hydroxymethyl cytosine (hmC), thereby leading to the demethylation of mC. In the seminar, I will also present some very exciting results we recently obtained on the functional characterization of Tet1.

 

References

1. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PAC, Rappsilber J and Helin K (2011). TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343-348

2. Pasini D, Cloos PAC, Walfridsson J, Olsson L, Bukowski J-P, Johansen JV, Bak M, Tommerup N, Rappsilber J and Helin K (2010). JARID2 regulates binding of the Polycomb Repressive Complex 2 to target genes in ES cells. Nature 464, 306-310

3. Agger K, Christensen J, Cloos PA, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE and Helin K (2007) UTX and JMJD3 are H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731-734.

4. Christensen J, Agger K, Cloos P, Pasini D, Rose S, Sennels L, Rappsilber J, Hansen KH, Salcini AE and Helin K (2007) RBP2 belongs to a family of demethylases specific for tri- and di-methylated lysine 4 on Histone 3. Cell, 128, 1063-1076.

Cloos PAC, Christensen J, Agger K, Maiolica A, Rappsibler J, Antal T, Hansen KH and Helin K (2006) The putative oncogene GASC1/JMJD2c demethylates tri- and di-methylated lysine 9 on histone H3, Nature 442, 307-311.