Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering. Issue 5 (May 2022)

• Record Type: Journal Article
• Authors: Franklin, Kierra A.; Shields, Cara E.; Haynes, Karmella A.
• Is Part Of: Trends in biochemical sciences. Volume 47:Issue 5(2022)
• Page Start: 417
• Page End: 432
• Publication Date: 2022-05
• Subjects: epigenome -- chromatin modifications -- transcriptional regulation -- cell developmental disease -- protein engineering -- signal integration; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2022.03.002
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Chromatin is a system of proteins and DNA that regulates chromosome organization and gene expression in eukaryotes. Essential features that support these processes include biochemical marks on histones and DNA, 'writer' enzymes that generate or remove these marks and proteins that translate the marks into transcriptional regulation: reader-effectors. Here, we review recent studies that reveal how reader-effectors drive chromatin-mediated processes. Advances in proteomics and epigenomics have accelerated the discovery of chromatin marks and their correlation with gene states, outpacing our understanding of the corresponding reader-effectors. Therefore, we summarize the current state of knowledge and open questions about how reader-effectors impact cellular function and human disease and discuss how synthetic biology can deepen our knowledge of reader-effector activity. Highlights: Mounting evidence associates reader-effectors to disease pathology and progression, and has brought more focus to chromatin reader-effectors as targets for therapies. Ongoing investigation of reader-effectors provides new insights into chromatin signaling mechanisms, such as recognition of histone H3(1–22) by the p300 ZZ domain. Reader-effectors have recently been discovered to modify other reader-effector proteins or generate covalent self-modifications. Wildtype and engineered reader domains have been repurposed as affinity agents for chromatin research, making them suitable alternatives to commercial antibodies. Synthetic covalent modification is the latest output that has been used to extend the utility of reader-effector-derived probes, and enables enhanced sensitivity and specificity for mapping the chromatin landscape. Epigenome actuation, the use of synthetic reader-effectors to transduce chromatin signals into gene regulation outputs, complements epigenome editing and addresses unmet needs in epigenetic engineering.