HP1a: a structural chromosomal protein regulating transcription

Abstract

Heterochromatin protein 1 (HP1a in Drosophila) is a conserved eukaryotic chromosomal protein that is prominently associated with pericentric heterochromatin and mediates the concomitant gene silencing. Mechanistic studies implicate HP1 family proteins as 'hub proteins,' able to interact with a variety of chromosomal proteins through the chromo-shadow domain (CSD), as well as to recognize key histone modification sites [primarily histone H3 di/trimethyl Lys9 (H3K9me2/3)] through the chromodomain (CD). Consequently, HP1 has many important roles in chromatin architecture and impacts both gene expression and gene silencing, utilizing a variety of mechanisms. Clearly, HP1 function is altered by context, and potentially by post-translational modifications (PTMs). Here, we report on recent ideas as to how this versatile protein accomplishes its diverse functions.

Keywords: HP1a; chromodomain; gene expression; silencing.

Figure 1

(A) Schematic representation of HP1 family proteins; example shown is HP1a from D. melanogaster (see text for abbreviations). (B) A 3-D model of the chromo domain, showing binding of the H3 N-terminal tail and the aromatic cage for K9me3 (image from [74]). (C) Alignment of the chromo domain from Homo sapiens CBX1, CBX5, and CBX3 with S. pombe Swi6, D. melanogaster HP1a, C. elegans HPL-2, and Arabadopsis thaliana LPH1. Amino acids are color-coded for functional similarity. The conserved residues that make up the aromatic cage are marked with an asterisk, and the position of V26 in HP1a, site of a loss-of-function mutation, is marked with a dot.

Figure 1

(A) Schematic representation of HP1 family proteins; example shown is HP1a from D. melanogaster (see text for abbreviations). (B) A 3-D model of the chromo domain, showing binding of the H3 N-terminal tail and the aromatic cage for K9me3 (image from [74]). (C) Alignment of the chromo domain from Homo sapiens CBX1, CBX5, and CBX3 with S. pombe Swi6, D. melanogaster HP1a, C. elegans HPL-2, and Arabadopsis thaliana LPH1. Amino acids are color-coded for functional similarity. The conserved residues that make up the aromatic cage are marked with an asterisk, and the position of V26 in HP1a, site of a loss-of-function mutation, is marked with a dot.

Figure 1

(A) Schematic representation of HP1 family proteins; example shown is HP1a from D. melanogaster (see text for abbreviations). (B) A 3-D model of the chromo domain, showing binding of the H3 N-terminal tail and the aromatic cage for K9me3 (image from [74]). (C) Alignment of the chromo domain from Homo sapiens CBX1, CBX5, and CBX3 with S. pombe Swi6, D. melanogaster HP1a, C. elegans HPL-2, and Arabadopsis thaliana LPH1. Amino acids are color-coded for functional similarity. The conserved residues that make up the aromatic cage are marked with an asterisk, and the position of V26 in HP1a, site of a loss-of-function mutation, is marked with a dot.

Figure 2

Cartoon models of a nucleosome array in which H3K9 is di- or trimethylated and bound by HP1. A. In this model, CSD-CSD homo-dimerization is indicated, which could facilitate chromatin condensation [31] and impose regular nucleosome positioning, as previously reported for HP1a-dependent transgene silencing in Drosophila [75]. B. In this model, based on studies on Swi6 in S. pombe, both CD-CD and CSD-CSD self-associations are indicated, which could facilitate further condensation of the chromatin fiber (model based on [32]).