Fact sheet 2: Histone modifications and Chromatin dynamics

Daniela Ramos-Cruz

In eukaryotes, DNA is tightly packed in the nucleus in a specific chromatin arrangement formed of nucleosomes. A nucleosome is the basic unit of DNA compaction and consists of 150 bp DNA wrapped around an octamer of histone proteins. Each octamer is composed of two copies of histones H2A, H2B, H3 and H4 and an intervening histone‐free linker DNA H1 (Luger et al., 1997). The level of chromatin compaction affects cellular processes such as transcription, replication or DNA repair by allowing the corresponding regulators to access the genetic information in response to developmental or environmental stimulus (Zhong et al., 2013).

Accessibility of chromatin is regulated by a set of protein complexes grouped in two classes, histone-modifying enzymes and ATP-dependent chromatin remodeling complexes. In this chapter we will describe the current knowledge about histone modifications and chromatin remodelers in the regulation of chromatin dynamics to control cellular responses.

Histone-modifying enzymes, post-translationally modify the N-terminal tails of histone proteins through acetylation, phosphorylation, ubiquitination, ADP-ribosylation and methylation. Histone modifications can be reversed by a set of antagonistic enzymes catalyzing the addition or removal of chemical modifications. The combinatorial arrangement of histone marks defines and partition the genome into functional domains, such as transcriptionally silent heterochromatin and transcriptionally active euchromatin. For example, histone acetylation has been linked to transcriptional activation, whereas histone ubiquitination and methylation has been observed in transcriptional activation and silencing. The inter-related collection of histone modifications forms the “histone code”, which is interpreted by effector proteins or “readers” that recognize and bind to modifications through specific domains, to further direct the different cellular responses dictated by the chromatin structure (Berr et al., 2011; Zhong et al, 2013; Strahl., 2000).

The second class of chromatin-modifying factors are the ATP-dependent chromatin-remodeling enzymes, which alter nucleosomal structure and DNA accessibility. ATP-dependent chromatin remodelers mediate gene activation by reposition (slide, twist, or loop) of nucleosomes along the DNA, by eviction of histones from DNA or by facilitating exchange of histone variants. Every chromatin remodeling complex contains a conserved ATPase subunit. Based on the similarity of the ATPase subunit and the presence of unique domains, such as cromodomains, bromodomains or PHD domains, chromatin remodelers are grouped into 4 different families (INO80/SWR1, CHD, ISWI and SNF/SNF) (Jarillo et al., 2009, Han et al., 2015). Remodelers of each family differ in their biochemical activity. For example, ISWI and CHD family participate in nucleosome spacing in chromatin assembly after replication (Corona and Tamkun, 2004); SWI/SNF subfamilies are important for nucleosomal disassembly (Whitehouse et al., 1999; Phelan et al., 2000), whereas INO80 and SWR1 complexes have opposite roles in histone variant exchange (Mizuguchi et al., 2004; Papamichos‐Chronakis et al., 2011).

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