The “Epigenetic Code Replication Machinery”, ECREM: A Promising Drugable Target of the Epigenetic Cell Memory

Christian      Bronner; Thierry      Chataigneau; Valerie   B.   Schini-Kerth; Yves      Landry

Abstract

Discrete chemical modifications of the chromatin (DNA and primarily histones) can regulate gene expression or repression and can be transmitted to the descent (cells or organisms) thanks to an epigenetic memory. These modifications involve histone posttranslational modifications, DNA methylation at CpG islands and small nuclear RNAs processes. They play fundamental roles in cell proliferation and differentiation. These two processes are crucial in particular during embryonic development, X chromosome inactivation in females, genomic imprinting, gene bookmarking, cell reprogramming, position effect and silencing of retroviral elements. While, only one major DNA modification is known, more than 150 post-translation modifications of histones have been reported, including methylations, acetylations, ubiquitinations, SUMOylations and phosphorylations. How these modifications are inherited from mother cells to daughter cells or from an organism to its descent remains a major scientific challenge. We propose here a macro-molecular complex, called ECREM for “Epigenetic Code REplication Machinery”, as being involved in the inheritance of the epigenetic code. The composition of ECREM may vary in a spatio-temporal manner according to the chromatin state, the cell phenotype and the development stage. We describe the members of ECREM, responsible for the epigenetic code inheritance, i.e., enzymes involved in DNA methylation and histone post-translational modifications. Some of them, such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACS including sirtuins), have been found to be deregulated in several types of pathologies and are already targeted by inhibitors. ECREM, thus, appears to be an interesting complex to be investigated in order to find new drugs for cancer, metabolic, neuro-degenerative and inflammatory diseases therapy.

Keywords: Cancer, DNA methyltransferase, drug, epigenetic, histone code, histone deacetylases, histone acetyltransferases, inhibitors, neuro-degenerative disorders, sirtuins