HP6/Umbrea, a rapidly evolving Drosophila HP1-family paralog, is a candidate HP1a-recruited plasticizer of heterochromatin

Abstract

HP6/Umbrea, a rapidly evolving Drosophila (Heterochromatin Protein 1) HP1-family paralog, has well-documented sequence and regulatory evolution but an under-studied molecular function. In this manuscript, we hypothesize that HP6/Umbrea acts as an HP1-recruited plasticizer, providing support for this model using coarse-grained molecular-dynamics simulations of HP1a condensates. Retaining only the dimerizing chromoshadow domain (CSD), HP6/Umbrea notably lacks independent chromatin-binding capacity but binds HP1a directly, co-localizing with it in vivo. We report that when covalently tethered to an HP1a carrier, HP6/Umbrea partitions into HP1a condensates ∼6-fold more strongly than when free, supporting HP1a-mediated recruitment as its entry route. Once incorporated, HP6/Umbrea leaves the phase-separation threshold, interfacial tension, and host partitioning statistically unchanged, but monotonically lowers dense-phase density. These observations are consistent with a spacer function rather than generic loss of cohesion. Importantly, unchanged short-time internal mobility suggests a packing effect, predicting increased permeability to large transcriptional machinery, potentially resulting in a position effect-variegation (PEV)-like modulation of heterochromatic silencing. Finally, comparative sequence analysis shows the C-terminal tail is a recently originated, purifying-selection-constrained innovation, which is consistent with an evolved function in this region. In sum, our simulations suggest a mechanistic basis for how HP6/Umbrea may have evolved as a condensate plasticizer and thus potentially act as a rheostat for leaky transcription. Author summary Heterochromatin, the densely packed, gene-silencing fraction of the genome, is organized in part by Heterochromatin Protein 1 (HP1), which has been described as forming liquid-like condensates. Drosophila carries a fast-evolving duplicate of HP1, called HP6/Umbrea, which has been extensively studied as a young gene under strong selection. It is known to interact with HP1 and other heterochromatin proteins, yet a mechanistic account of what it does, especially the biochemical function that natural selection could act on, has remained lacking. HP6/Umbrea is a truncated protein that retains only the domain that lets HP1 proteins pair up, having lost the parts that read and bind chromatin. Using physics-based simulations of the HP1 condensate, our simulations indicate that this reduced structure has a simple consequence: HP6/Umbrea cannot enter heterochromatin on its own but is carried in by pairing with HP1, and once inside it loosens the interior packing without changing the condensate’s boundary or its tendency to form. We propose that HP6/Umbrea acts like a plasticizer, a molecular softener that could make otherwise silenced heterochromatic genes leakier (e.g., more widespread transcription) and thereby tune repression.