Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites

Liu, Ce Feng; Brandt, Gabriel S.; Hoang, Quyen Q.; Naumova, Natalia; Lazarevic, Vanja; Hwang, Eun Sook; Dekker, Job; Glimcher, Laurie H.; Ringe, Dagmar; Petsko, Gregory A.

doi:10.1073/pnas.1613914113

Title: Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites

Journal Article · Mon Oct 10 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1613914113· OSTI ID:1333416

Liu, Ce Feng ^[1]; Brandt, Gabriel S. ^[2]; Hoang, Quyen Q. ^[3]; Naumova, Natalia ^[4]; Lazarevic, Vanja ^[5]; Hwang, Eun Sook ^[6]; Dekker, Job ^[7]; Glimcher, Laurie H. ^[8]; Ringe, Dagmar ^[9]; Petsko, Gregory A. ^[1]

Weill Cornell Medical College, New York, NY (United States); Brandeis Univ., Waltham, MA (United States)
Brandeis Univ., Waltham, MA (United States); Franklin and Marshall College, Lancaster, PA (United States)
Brandeis Univ., Waltham, MA (United States); Indiana Univ. School of Medicine, Indianapolis, IN (United States)
Univ. of Massachusetts Medical School, Worcester, MA (United States); Epinomics, Menlo Park, CA (United States)
Harvard Medical School, Boston, MA (United States); National Cancer Inst./National Inst. of Health, Bethesda, MD (United States)
Harvard Medical School, Boston, MA (United States); Ewha Womans Univ., Seoul (Korea)
Univ. of Massachusetts Medical School, Worcester, MA (United States)
Harvard Medical School, Boston, MA (United States); Ragon Inst. of Massachusetts Inst. of Technology, Massachusetts General Hospital, and Harvard Univ., Charlestown, MA (United States); Dana Farber Cancer Inst., Boston, MA (United States)
Brandeis Univ., Waltham, MA (United States)

The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the T_H1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We have determined the crystal structure of the Tbox DNA binding domain (DBD) of T-bet in complex with a palindromic DNA. The structure shows a quaternary structure in which the T-bet dimer has its DNA binding regions splayed far apart, making it impossible for a single dimer to bind both sites of the DNA palindrome. In contrast to most other Tbox proteins, a single T-bet DBD dimer binds simultaneously to identical half-sites on two independent DNA. A fluorescence-based assay confirms that T-bet dimers are able to bring two independent DNA molecules into close juxtaposition. Furthermore, chromosome conformation capture assays confirm that T-bet functions in the direct formation of chromatin loops in vitro and in vivo. Here, the data are consistent with a looping/synapsing model for transcriptional regulation by T-bet in which a single dimer of the transcription factor can recognize and coalesce distinct genetic elements, either a promoter plus a distant regulatory element, or promoters on two different genes.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH); National Cancer Inst.; National Inst. of General Medical Sciences

Grant/Contract Number:: AC02-06CH11357; P01-AI056296; 5F32GM069057; ACB-12002; AGM-12006

OSTI ID:: 1333416

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 43; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 14 works

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Title: Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites

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