Showing papers by "Jacques Côté published in 2014"

Histone target selection within chromatin: an exemplary case of teamwork

Abstract: Histone modifiers like acetyltransferases, methyltransferases, and demethylases are critical regulators of most DNA-based nuclear processes, de facto controlling cell cycle progression and cell fate. These enzymes perform very precise post-translational modifications on specific histone residues, which in turn are recognized by different effector modules/proteins. We now have a better understanding of how these enzymes exhibit such specificity. As they often reside in multisubunit complexes, they use associated factors to target their substrates within chromatin structure and select specific histone mark-bearing nucleosomes. In this review, we cover the current understanding of how histone modifiers select their histone targets. We also explain how different experimental approaches can lead to conflicting results about the histone specificity and function of these enzymes.

Crosstalk between epigenetic readers regulates the MOZ/MORF HAT complexes

Abstract: The MOZ/MORF complexes represent an example of a chromatin-binding assembly whose recruitment to specific genomic regions and activity can be fine-tuned by posttranslational modifications of histones. Here we detail the structures and biological functions of epigenetic readers present in the four core subunits of the MOZ/MORF complexes, highlight the imperative role of combinatorial readout by the multiple readers, and discuss new research directions to advance our understanding of histone acetylation.

Eaf5/7/3 form a functionally independent NuA4 submodule linked to RNA polymerase II-coupled nucleosome recycling

Abstract: The NuA4 histone acetyltransferase complex is required for gene regulation, cell cycle progression, and DNA repair. Dissection of the 13-subunit complex reveals that the Eaf7 subunit bridges Eaf5 with Eaf3, a H3K36me3-binding chromodomain protein, and this Eaf5/7/3 trimer is anchored to NuA4 through Eaf5. This trimeric subcomplex represents a functional module, and a large portion exists in a native form outside the NuA4 complex. Gene-specific and genome-wide location analyses indicate that Eaf5/7/3 correlates with transcription activity and is enriched over the coding region. In agreement with a role in transcription elongation, the Eaf5/7/3 trimer interacts with phosphorylated RNA polymerase II and helps its progression. Loss of Eaf5/7/3 partially suppresses intragenic cryptic transcription arising in set2 mutants, supporting a role in nucleosome destabilization. On the other hand, loss of the trimer leads to an increase of replication-independent histone exchange over the coding region of transcribed genes. Taken together, these results lead to a model where Eaf5/7/3 associates with elongating polymerase to promote the disruption of nucleosomes in its path, but also their refolding in its wake.

Regulating Chromatin by Histone Acetylation

Abstract: Acetylation of lysine residues on histones has been known for almost 50 years and is the most characterized posttranslational modification of chromatin. It is known to have a direct impact on the structure of chromatin as well as to play a signaling role to regulate the association of factors to specific genomic loci. Thus, it is not surprising that histone acetylation plays critical regulatory roles in all major nuclear processes, including gene expression, DNA repair, and replication. Here, we present an overview of the current state of knowledge on the role of histone acetylation in chromatin structure and function during DNA-based processes. We cover the functions of protein complexes involved in the addition and the removal of this mark on chromatin and how it is recognized as a signal. We also present how acetylation is functionally linked to other histone modifications. Finally, we discuss recent developments connecting histone acetylation to metabolism and aging as well as targeted drug discoveries aimed at treating human diseases.

A new companion of elongating RNA Polymerase II: TINTIN, an independent sub-module of NuA4/TIP60 for nucleosome transactions.

Abstract: Multiple factors are involved in the elongation stage of transcription regulation to ensure the passing of RNA polymerases while preserving appropriate nucleosome structure thereafter. The recently reported trimeric sub-module of NuA4 histone acetyltransferase complex involved in this process provides more insight into the sophisticated modulation of transcription elongation.

DNA repair: Chromatin remodeling without H2A.Z?

Abstract: Chromatin is a highly dynamic structure regulated by different factors, such as ATP-dependent remodeling complexes, incorporation of histone variants, post-translational modifications, and histones chaperones. During the DNA damage response, the chromatin architecture must be transiently and locally modified in order to regulate access to the DNA lesion. Chromatin remodeling at double-strand breaks is necessary, and the recruitment of remodeler complexes such as INO80, SWI/SNF-BRG1-RSC, FUN30, as well as the SWR1/p400 has been observed. Post-translational modifications of histones, such as phosphorylation, ubiquitination, and acetylation at sites of damage are also important to regulate the subsequent repair and cell cycle checkpoint activation/release. Moreover the H2A variant H2A.X is a well-documented player whose phosphorylation is a primary event to initiate the signaling cascade and stabilize the association of multiple factors.