Functions of HP1 proteins in transcriptional regulation

Abstract

In eukaryotes, DNA is packaged into chromatin, which presents significant barriers to transcription. Non-histone chromatin proteins such as the Heterochromatin Protein 1 (HP1) proteins are critical regulators of transcription, contributing to gene regulation through a variety of molecular mechanisms. HP1 proteins are highly conserved, and many eukaryotic genomes contain multiple HP1 genes. Given the presence of multiple HP1 family members within a genome, HP1 proteins can have unique as well as shared functions. Here, we review the mechanisms by which HP1 proteins contribute to the regulation of transcription. Focusing on the Drosophila melanogaster HP1 proteins, we examine the role of these proteins in regulating the transcription of genes, transposable elements, and piRNA clusters. In D. melanogaster, as in other species, HP1 proteins can act as transcriptional repressors and activators. The available data reveal that the precise impact of HP1 proteins on gene expression is highly context dependent, on the specific HP1 protein involved, on its protein partners present, and on the specific chromatin context the interaction occurs in. As a group, HP1 proteins utilize a variety of mechanisms to contribute to transcriptional regulation, including both transcriptional (i.e. chromatin-based) and post-transcriptional (i.e. RNA-based) processes. Despite extensive studies of this important protein family, open questions regarding their functions in gene regulation remain, specifically regarding the role of hetero- versus homodimerization and post-translational modifications of HP1 proteins.

Epigenetic control of myogenic identity of human muscle stem cells in Duchenne Muscular Dystrophy

“…In the absence of SMC3, a loss of Topological Associated Domains (TADs) in the DMD-MuSCs would prevent the muscle-specific enhancers from communicating with promoters, and would result in a reduction of muscle gene expression. Similarly, CBX3 is required to maintain high levels of muscle gene expression as the euchromatin-associated protein helps facilitate transcriptional elongation by promoting RNA Polymerase II pause-release and recruitment of the FACT complex required for removal of nucleosomes that impede polymerase progression (Yahi et al 2008;Kim et al 2011;Zhong et al 2019;Schoelz and Riddle 2022). Finally, the histone variants H2A.Z2 and H3.3 proteins promote a transcriptionally permissive chromatin state by establishing a less stable nucleosome that is easily displaced by chromatin remodeling factors to establish open chromatin (Santisteban et al 2000;Jin et al 2009;Vardabasso et al 2015).…”

Endogenous Retroviral Sequences Behave as Putative Enhancers Controlling Gene Expression through HP1-Regulated Long-Range Chromatin Interactions

“…The role of the HP1 proteins as activating or repressing factors for endogenous gene regulation, as well as for the silencing of transposable elements, remains highly debated (for a recent review, see [ 29 ]). In this regard, relevant studies in model organisms such as Drosophila can help the interpretation of experiments performed in more complex genomes such as those of mammals.…”

“…Interestingly, different mechanisms of the HP1-dependent silencing of transposable elements have been proposed in Drosophila , including the direct binding of HP1 to the transposable elements as in the case of the gypsy-like element, ZAM [ 33 ], or by allowing the expression of small RNAs that themselves will silence the expression of the transposable elements in the case of piRNAs clusters [ 34 ]. In mammals, different mechanisms of silencing transposable elements have also been described, the best characterised involving the corepressor TRIM28 and its interaction with HP1 [ 7 , 29 ]. Our work links the roles of HP1 in the control of transposable elements and endogenous gene regulation.…”

Uncoupling the distinct functions of HP1 proteins during heterochromatin establishment and maintenance

“…According to these models, HP1 condensates selectively include heterochromatin associated proteins while excluding proteins that promote RNA polymerase II activity. Because of these wide-ranging biophysical properties of HP1 proteins, all models of heterochromatin are premised on HP1 proteins being absolutely essential for transcriptional silencing (Nishibuchi and Nakayama, 2014;Larson and Narlikar, 2018;Kumar and Kono, 2020;Schoelz and Riddle, 2022).…”

“…[19][20][21] Because of these wide-ranging biophysical properties of HP1 proteins, all models of heterochromatin are premised on HP1 proteins being essential for transcriptional silencing. [22][23][24][25] In Schizosaccharomyces pombe (S.pombe), H3K9me marks constitutive heterochromatin regions, including the pericentromeric repeats flanking centromeres, telomeres, and the mating type locus. 26 The enzyme Clr4 catalyzes H3K9 methylation, which leads to binding of two conserved HP1 proteins, Swi6 and Chp2.…”