The Histone Code of Senescence

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response

Computational Study on Protein Arginine methyl-transferases (PRMTs)

Protein arginine methyltransferases (PRMTs) are essential epigenetic players in living cells. The dysregulation of PRMTs is closely related to many diseases, including cancer. Based on previously reported PRMT1 inhibitors bearing the diamidine pharmacophore, a combinatorial high throughput screening strategy led to compound K313, which possesses a biochemical IC50 value of 0.84 µM against PRMT1. Histone code is the post-translational modification patterns appear at histone, which regulates transcription and many other cellular events. H4R3 is one of the important substrates for both PRMT1 and PRMT5. PRMTs are important in establishing histone code. They are also regulated by the histone code. In this study, we explored the mechanism of how the post-translational modifications on H4 tail peptide affect the activity of PRMTs

Chemical Cryptology of Cancer’s Histone Code

Somatic mutations in non-Hodgkin's lymphoma frequently activate EZH2, a protein methyltransferase responsible for H3K27 trimethylation. In this issue of Chemistry and Biology, Bradley and coworkers describe a new set of EZH2 inhibitors amenable to probing the targetable role of H3K27 trimethylation in lymphoma

Histone code, human growth and cancer

Epigenetics refers to all heritable changes, which are not dependent on alterations of DNA primary structure [1]. Among them, histone post-translational modifications (HPTMs) play a crucial role in regulating gene expression. Histones are core chromatin components, organized in cylindrical structures. The nucleosome is the fundamental chromatin unit: it is made of appreciatively 150 bp. DNA wrapped around a cylindrical histone core [2]. Histone N-terminal tails protrude from this compact structure, and may be modified by several HPTMs (acetylation, methylation, phosphorylation…). Each modification occurs on a specific residue, and is mediated by an enzymatic complex. Since HPTMs dictate DNA-chromatin binding and gene activity, it has been proposed that a complex histone code orchestrates gen

Phosphorylation of SU(VAR)3-9 by the chromosomal kinase JIL-1

The histone methyltransferase SU(VAR)3-9 plays an important role in the formation of heterochromatin within the eukaryotic nucleus. Several studies have shown that the formation of condensed chromatin is highly regulated during development, suggesting that SU(VAR)3-9's activity is regulated as well. However, no mechanism by which this may be achieved has been reported so far. As we and others had shown previously that the N-terminus of SU(VAR)3-9 plays an important role for its activity, we purified interaction partners from Drosophila embryo nuclear extract using as bait a GST fusion protein containing the SU(VAR)3-9 N-terminus. Among several other proteins known to bind Su(VAR)3-9 we isolated the chromosomal kinase JIL-1 as a strong interactor. We show that SU(VAR)3-9 is a substrate for JIL-1 in vitro as well as in vivo and map the site of phosphorylation. These findings may provide a molecular explanation for the observed genetic interaction between SU(VAR)3-9 and JIL-1

Coordinated actions of microRNAs with other epigenetic factors regulate skeletal muscle development and adaptation

Epigenetics plays a pivotal role in regulating gene expression in development, in response to cellular stress or in disease states, in virtually all cell types. MicroRNAs (miRNAs) are short, non-coding RNA molecules that mediate RNA silencing and regulate gene expression. miRNAs were discovered in 1993 and have been extensively studied ever since. They can be expressed in a tissue-specific manner and play a crucial role in tissue development and many biological processes. miRNAs are responsible for changes in the cell epigenome because of their ability to modulate gene expression post-transcriptionally. Recently, numerous studies have shown that miRNAs and other epigenetic factors can regulate each other or cooperate in regulating several biological processes. On the one hand, the expression of some miRNAs is silenced by DNA methylation, and histone modifications have been demonstrated to modulate miRNA expression in many cell types or disease states. On the other hand, miRNAs can directly target epigenetic factors, such as DNA methyltransferases or histone deacetylases, thus regulating chromatin structure. Moreover, several studies have reported coordinated actions between miRNAs and other epigenetic mechanisms to reinforce the regulation of gene expression. This paper reviews multiple interactions between miRNAs and epigenetic factors in skeletal muscle development and in response to stimuli or disease