Nucleosome compaction facilitates HP1γ binding to methylated H3K9

Area of Science:

• Epigenetics
• Molecular Biology
• Chromatin Biology

Background:

• Mammalian heterochromatin protein 1 (HP1) isoforms (α, β, γ) bind to methylated lysine 9 of histone H3 through their chromodomains.
• Distinct phenotypes of HP1-knockout mice suggest isoform-specific functions, but the underlying molecular mechanisms are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms behind the distinct functions of HP1 isoforms, specifically focusing on the differential recognition of histone modifications.
• To elucidate how nucleosome structure influences the binding preferences of HP1α and HP1γ to methylated histone H3 lysine 9.

Main Methods:

• Reconstituted tetra-nucleosomes were used to study the binding of HP1 isoforms to tri-methylated H3 lysine 9 in both uncompacted and compacted states.
• The role of the hinge region connecting the chromodomain and chromoshadow domain in HP1 isoform recognition was examined.
• The effect of Mg(2+) and linker histone H1 on HP1 isoform binding was assessed to understand their influence on nucleosome compaction.

Main Results:

• HP1γ, unlike HP1α, failed to bind tri-methylated H3 lysine 9 in uncompacted nucleosomes.
• The hinge region of HP1 isoforms was identified as a key determinant for differential nucleosome recognition.
• HP1γ's binding to tri-methylated H3 lysine 9 was significantly enhanced by Mg(2+) or linker histone H1, which induce nucleosome compaction, whereas HP1α binding was not similarly affected.

Conclusions:

• HP1γ exhibits a unique ability to recognize tri-methylated H3 lysine 9 in compacted nucleosome structures, a property not shared by HP1α.
• The differential recognition of histone H3 lysine 9 based on nucleosome structure, mediated by the hinge region, highlights a novel mechanism for HP1 isoform-specific function.
• This distinct nucleosome recognition property of HP1γ is proposed to be crucial for interpreting the histone code in different chromatin contexts.