2. Academic Validation
  3. A short ORF-encoded transcriptional regulator

A short ORF-encoded transcriptional regulator

  • Proc Natl Acad Sci U S A. 2021 Jan 26;118(4):e2021943118. doi: 10.1073/pnas.2021943118.
Minseob Koh 1 2,  Insha Ahmad 1,  Yeonjin Ko 1,  Yuxiang Zhang 1,  Thomas F Martinez 3,  Jolene K Diedrich 3,  Qian Chu 3,  James J Moresco 3,  Michael A Erb 1,  Alan Saghatelian 4,  Peter G Schultz 5,  Michael J Bollong 5
Affiliations

Affiliations

  • 1 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
  • 2 Department of Chemistry, Pusan National University, Busan 46241, Republic of Korea.
  • 3 Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037.
  • 4 Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037 asaghatelian@salk.edu schultz@scripps.edu mbollong@scripps.edu.
  • 5 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; asaghatelian@salk.edu schultz@scripps.edu mbollong@scripps.edu.
PMID: 33468658 DOI: 10.1073/pnas.2021943118
Abstract

Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame (ORF)-encoded Peptides (SEPs) have now been found to be translated. Although several studies have identified important physiological roles for this emerging protein class, a general method to define their interactomes is lacking. Here, we demonstrate that genetic incorporation of the photo-crosslinking noncanonical amino acid AbK into SEP transgenes allows for the facile identification of SEP cellular interaction partners using affinity-based methods. From a survey of seven SEPs, we report the discovery of short ORF-encoded histone binding protein (SEHBP), a conserved microprotein that interacts with chromatin-associated proteins, localizes to discrete genomic loci, and induces a robust transcriptional program when overexpressed in human cells. This work affords a straightforward method to help define the physiological roles of SEPs and demonstrates its utility by identifying SEHBP as a short ORF-encoded transcription factor.

Keywords

expanded genetic code; photo-crosslinking; short open reading frame-encoded peptide; transcriptional regulation.

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