Abstract
Recognition of histone post-translational modifications is pivotal for directing chromatin-modifying enzymes to specific genomic regions and regulating their activities. Emerging evidence suggests that other structural features of nucleosomes also contribute to precise targeting of downstream chromatin complexes, such as linker DNA, the histone globular domain, and nucleosome spacing. However, how chromatin complexes coordinate individual interactions to achieve high affinity and specificity remains unclear. The Rpd3S histone deacetylase utilizes the chromodomain-containing Eaf3 subunit and the PHD domain-containing Rco1 subunit to recognize nucleosomes that are methylated at lysine 36 of histone H3 (H3K36me). We showed previously that the binding of Eaf3 to H3K36me can be allosterically activated by Rco1. To investigate how this chromatin recognition module is regulated in the context of the Rpd3S complex, we first determined the subunit interaction network of Rpd3S. Interestingly, we found that Rpd3S contains two copies of the essential subunit Rco1, and both copies of Rco1 are required for full functionality of Rpd3S. Our functional dissection of Rco1 revealed that besides its known chromatin-recognition interfaces, other regions of Rco1 are also critical for Rpd3S to recognize its nucleosomal substrates and functionin vivo. This unexpected result uncovered an important and understudied aspect of chromatin recognition. It suggests that precisely reading modified chromatin may not only need the combined actions of reader domains but also require an internal signaling circuit that coordinates the individual actions in a productive way.
Highlights
It is widely accepted that histone post-translational modifications (PTMs)2 and other structural features of chromatin, such as variant histones and DNA modifications, mainly serve as signal platforms to direct downstream regulatory events [1, 2]
Modified histone peptides can be recognized by protein domains/motifs that are commonly referred as PTM “readers.” A large repertoire of such domain/PTM interactions have been documented, and they are essential for targeting downstream factors to a given genomic locus [3]
Because PTMs are mostly clustered at structurally flexible histone tails, it has been postulated that globular contact is needed as a stable anchor to properly orient chromatin binders on their substrates [5]
Summary
It is widely accepted that histone post-translational modifications (PTMs)2 and other structural features of chromatin, such as variant histones and DNA modifications, mainly serve as signal platforms to direct downstream regulatory events [1, 2]. Two key components of Rpd3S that were shown to involve chromatin recognition are Eaf3, which contains a chromodomain (CHD) that binds to H3K36me, and Rco1, which contains two PHD domains with PHD1 being essential for Rpd3S function [11]. Deletion of the SID domain from one copy of Rco1 is sufficient to abolish nucleosome binding ability of Rpd3S without disrupting the integrity of the complex.
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