HP1: heterochromatin binding proteins working the genome

Abstract

Heterochromatin Protein 1 (HP1) is a transcriptional repressor that directly binds to the methylated lysine 9 residue of histone H3 (H3K9me), which is a hallmark histone modification for transcriptionally silenced heterochromatin. Studies of homologs in different organisms have provided significant insight into the function of HP1 and the role of H3K9me. Initially discovered to be a major constituent of heterochromatin important for gene silencing, HP1 is now known to be a dynamic protein that also functions in transcriptional elongation, centromeric sister chromatid cohesion, telomere maintenance and DNA repair. Furthermore, recent studies have begun to uncover functional differences between HP1 variants and their H3K9me-independent mode of action. As our understanding of HP1 expands, however, conflicting data has also been reported that requires further reconciliation. Here we focus on some of the recent findings and controversies concerning HP1 functions in mammalian cells in comparison to studies in other organisms.

Figure 1

Alignment of HP1 amino acid sequences. All available HP1 amino acid sequences are from the NCBI protein sequence database. In the alignment results, besides the chromo domain (CD) and the chromo shadow domain (CSD), the N-terminus adjacent to the CD, the C-terminus adjacent to the CSD, and the middle fragment between the two domains (i.e., the linker/hinge domain) are compared between the different proteins. Therefore, each protein diagram is separated into five fragments and in each fragment, the degree of homology is indicated with different colors. The length of each diagram is proportional to the protein size. (A) Alignment of mammalian HP1 amino acid sequences. The sequences of mammalian HP1β and HP1γ are compared with HP1α. The percentage of homology is based on comparison to HP1α (indicated in white/gray). (B) Alignment of HP1 amino acid sequences between different species. The HP1 amino acid sequences from several non-mammalian species are compared to the corresponding mammalian HP1 variant and their homology with mammalian HP1 is indicated in the color diagram. For C. elegans, S. pombe and A. thaliana, the homology between their HP1 proteins and each individual mammalian HP1 variant is low. Therefore, in the diagram, their sequences are compared to the mammalian HP1 variant with the highest alignment score. The alignment of the chromo and chromo shadow domains is delineated with dashed lines. Since all three mammalian HP1 sequences are used as standards for the individual alignments, they are all shown in white/gray.

Figure 2

Relationship between HP1 and cohesin. The sequential recruitment of Swi6/HP1 and cohesin to S. pombe pericentromeric heterochromatin regions (left) and the interdependent recruitment of HP1γ and cohesin to human D4Z4 repeats (right) are depicted.