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.

Fig. 1

Position effect variegation in Drosophila. The normally euchromatic white gene is placed close to the pericentric heterochromatin due to X-ray induced chromosome inversion. During early Drosophila development, heterochromatin spreading in some progenitor cells results in the silencing of white. Such expression is clonally inherited in all the progenies of the same cell, resulting in white patches of the adult eye

Fig. 2

The stepwise assembly of heterochromatin in budding yeast. a Heterochromatin establishment is achieved by targeting of the Sir protein complex to telomeres or silencers at the silent mating type locus through DNA-binding proteins where Sir2 deacetylates H4K16. b Deacetylated histones increase the affinity of Sir3 and Sir4 for chromatin and recruit additional Sir complex. Sir2 then deacetylates adjacent nucleosomes to allow heterochromatin spreading. c The formation of an extend heterochromatin domain that is covered by Sir complex

Fig. 3

The establishment and spreading of heterochromatin in fission yeast. a Heterochromatin establishment is achieved by sequence-specific DNA-binding proteins or RNAi-mediated targeting of histone methyltransferase CLRC to repetitive DNA elements, leading to local H3K9 methylation. b H3K9me recruits Swi6, which might facilitate the recruitment of additional CLRC. The chromodomain of Clr4 also recognizes H3K9me and facilitates CLRC recruitment. CLRC then methylates adjacent nucleosomes, leading to heterochromatin spreading. SHREC associates with Swi6 and deacetylate histones to promote heterochromatin spreading. c The formation of an extended heterochromatin domain that is covered by Swi6, CLRC and SHREC

Fig. 4

Mechanism of boundary function. a Boundary elements recruit histone-modifying activities. b Boundary elements recruit proteins that protect euchromatic modifications. c Nucleosome-free regions prevent the spreading of heterochromatin modifications to establish heterochromatin boundaries. d High rate of histone turnover prevents the spreading of histone modifications. e RNA-mediated eviction of heterochromatin protein Swi6 to prevent heterochromatin spreading. f Boundary elements cluster and associate with nuclear structures to form chromatin loops