Short tandem repeats bind transcription factors to tune eukaryotic gene expression-Reference-Cited by-同舟云学术

Short tandem repeats bind transcription factors to tune eukaryotic gene expression

Published:2023-09-22 Issue:6664 Volume:381 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Horton Connor A.¹^ORCID,Alexandari Amr M.²^ORCID,Hayes Michael G. B.¹^ORCID,Marklund Emil¹^ORCID,Schaepe Julia M.³^ORCID,Aditham Arjun K.³⁴^ORCID,Shah Nilay⁵^ORCID,Suzuki Peter H.³^ORCID,Shrikumar Avanti²^ORCID,Afek Ariel⁶⁷⁸^ORCID,Greenleaf William J.¹^ORCID,Gordân Raluca⁶⁷⁹¹⁰,Zeitlinger Julia⁵¹¹^ORCID,Kundaje Anshul¹²^ORCID,Fordyce Polly M.¹³⁴¹²^ORCID

Affiliation:

1. Department of Genetics, Stanford University, Stanford, CA 94305, USA.

2. Department of Computer Science, Stanford University, Stanford, CA 94305, USA.

3. Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.

4. ChEM-H Institute, Stanford University, Stanford, CA 94305, USA.

5. Stowers Institute for Medical Research, Kansas City, MO 64110, USA.

6. Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, NC 27710, USA.

7. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA.

8. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.

9. Department of Computer Science, Duke University, Durham, NC 27708, USA.

10. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.

11. The University of Kansas Medical Center, Kansas City, KS 66103, USA.

12. Chan Zuckerberg Biohub, San Francisco, CA 94110, USA.

Abstract

Short tandem repeats (STRs) are enriched in eukaryotic cis -regulatory elements and alter gene expression, yet how they regulate transcription remains unknown. We found that STRs modulate transcription factor (TF)–DNA affinities and apparent on-rates by about 70-fold by directly binding TF DNA-binding domains, with energetic impacts exceeding many consensus motif mutations. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density, with impacts well predicted by statistical mechanics. Confirming that STRs also affect TF binding in cells, neural networks trained only on in vivo occupancies predicted effects identical to those observed in vitro. Approximately 90% of TFs preferentially bound STRs that need not resemble known motifs, providing a cis -regulatory mechanism to target TFs to genomic sites.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.add1250

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