Chromosome boundary elements and regulation of heterochromatin spreading

Abstract

Chromatin is generally classified as euchromatin or heterochromatin, each with distinct histone modifications, compaction levels, and gene expression patterns. Although the proper formation of heterochromatin is essential for maintaining genome integrity and regulating gene expression, heterochromatin can also spread into neighboring regions in a sequence-independent manner, leading to the inactivation of genes. Because the distance of heterochromatin spreading is stochastic, the formation of boundaries, which block the spreading of heterochromatin, is critical for maintaining stable gene expression patterns. Here we review the current understanding of the mechanisms underlying heterochromatin spreading and boundary formation.

New Insights into the Regulation of Heterochromatin

“…For example, in constitutive heterochromatic regions histones are generally hypo-acetylated and hyper-methylated at H3 lysine 9 (H3K9me) [5–7]. The formation of these heterochromatin domains requires concerted actions of chromatin-modifying enzymes and is distinguished into three steps: initiation, spreading, and maintenance [8] (Fig. 1).…”

The proper connection between shelterin components is required for telomeric heterochromatin assembly

“…Heterochromatin has the propensity to spread from the site of initiation to neighboring regions generally in a sequence-independent manner (Wang et al 2014a). However, the failure of CLRC to spread from the site of recruitment (the Tpz1-Pot1 subcomplex located at the ssDNA of telomeres) over telomeric repeats to more internal regions in mutations that disrupt interactions between shelterin subunits suggests that telomeric repeats are refractory to heterochromatin spreading.…”

“…These heterochromatic regions are associated with distinct histone modification profiles and chromatin proteins, including low levels of acetylation, high levels of methylation at histone H3 Lys9 (H3K9me), and heterochromatin protein 1 (HP1) family proteins (Grewal and Jia 2007). Heterochromatin formation requires concerted actions of diverse histone-modifying activities, which are classified into three distinct steps: initiation, spreading, and maintenance (Wang et al 2014a). Initiation of heterochromatin assembly takes place at nucleation centers via targeting of histone H3K9 methyltransferases by sequence-specific DNA-binding proteins or noncoding RNAs, leading to H3K9me (Castel and Martienssen 2013;Cohen and Jia 2014).…”

“…Initiation of heterochromatin assembly takes place at nucleation centers via targeting of histone H3K9 methyltransferases by sequence-specific DNA-binding proteins or noncoding RNAs, leading to H3K9me (Castel and Martienssen 2013;Cohen and Jia 2014). Heterochromatin then spreads from these nucleation centers through a positive feedback loop involving H3K9me-mediated recruitment of additional histone H3K9 methyltransferases that methylate adjacent nucleosomes, resulting in an "inch worm"-like spreading (Talbert and Henikoff 2006;Wang et al 2014a). Similarly, the recruitment of H3K9 methyltransferases by pre-existing H3K9me on old histones allows the newly incorporated histones during DNA replication to be methylated as well, resulting in stable maintenance of heterochromatin domains through cell divisions even without the initiation signal (Audergon et al 2015;Ragunathan et al 2015).…”

The Epigenetic Pathways to Ribosomal DNA Silencing

“…Various characteristic chromatin modifications of histones in eukaryotes are known to contribute to the assembly of heterochromatin, the stability of the genome, and the restriction of heterochromatin spreading into adjacent chromatin domains (4).…”