Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: A molecular model for the formation of heterochromatin in yeast

Abstract

The silent mating loci and chromosomal regions adjacent to telomeres of S. cerevisiae have features similar to heterochromatin of more complex eukaryotes. Transcriptional repression at these sites depends on the silent information regulators SIR3 and SIR4 as well as histones H3 and H4. We show here that the SIR3 and SIR4 proteins interact with specific silencing domains of the H3 and H4 N-termini in vitro. Certain mutations in these factors, which affect their silencing functions in vivo, also disrupt their interactions in vitro. Immunofluorescence studies with antibodies against RAP1 and SIR3 demonstrate that the H3 and H4 N-termini are required for the association of SIR3 with telomeric chromatin and the perinuclear positioning of yeast telomeres. Based on these interactions, we propose a model for heterochromatin-mediated transcriptional silencing in yeast, which may serve as a paradigm for other eukaryotic organisms as well.

Epigenetic inheritance: Uncontested?

“…Certain histone modification events, including H4K16 deacetylation, H3K9 methylation and H3K27 methylation, can spread along the chromatin to maintain a regional heterochromatic environment [63][64][65]. These events are typically mediated by the association of a chromatin-modifying enzyme with a partner effector protein that specifically recognizes the modified product, such as Sir2 (H4K16 deacetylase) [66] with Sir3 (H4K16 effector) [67], Suvar39/Clr4 (H3K9 methyltransferase) [5,68] with HP1/Swi6 (H3K9me3 effector) [6,7,68], and PRC2-Ezh2 (H3K27 methyltransferase) [8][9][10][11] with Eed, a subunit of PRC2 as the H3K27me3 effector [50,65]. Therefore, inheritance of histone modifications can be achieved through similar biochemical mechanisms.…”

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

“…Another example is that of the yeast Sir3 factor involved in the recruitment of Sir2 to chromatin and the spreading of heterochromatin through binding with H4. In this case, acetylation of H4K16 abrogates Sir3 binding, thereby limiting the spreading of silenced chromatin (Hecht et al, 1995;Carmen et al, 2002;Kimura et al, 2002;Suka et al, 2002).…”

Groucho proteins: transcriptional corepressors for specific subsets of DNA-binding transcription factors in vertebrates and invertebrates

“…An interaction with histone H3 could lead to the assembly or stabilization of repressive chromatin on target gene promoters and thereby repress transcription. This mechanism is used by the SIR repressors from yeast (Hecht et al 1995), but for the Groucho proteins the role of the interaction with H3 in transcriptional repression is untested (Palaparti et al 1997). The Groucho proteins may also work by other mechanisms in addition to, or instead of, the assembly of chromatin.…”