A short ORF-encoded transcriptional regulator

Minseob Koh, Insha Ahmad, Yeonjin Ko, Yuxiang Zhang, Thomas F. Martinez, Jolene K. Diedrich, Qian Chu, James J. Moresco, Michael A. Erb, Alan Saghatelian, Peter G. Schultz, Michael J. Bollong

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Article numbere2021943118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
StatePublished - Jan 26 2021
Externally publishedYes


  • Expanded genetic code
  • Photo-crosslinking
  • Short open reading frame-encoded peptide
  • Transcriptional regulation

ASJC Scopus subject areas

  • General


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