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Logic and lineage impacts on functional transcription factor deployment for T-cell fate commitment

Rothenberg, Ellen V. (2021) Logic and lineage impacts on functional transcription factor deployment for T-cell fate commitment. Biophysical Journal, 120 (19). pp. 4162-4181. ISSN 0006-3495. doi:10.1016/j.bpj.2021.04.002.

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Transcription factors are the major agents that read the regulatory sequence information in the genome to initiate changes in expression of specific genes, both in development and in physiological activation responses. Their actions depend on site-specific DNA binding and are largely guided by their individual DNA target sequence specificities. However, their action is far more conditional in a real developmental context than would be expected for simple reading of local genomic DNA sequence, which is common to all cells in the organism. They are constrained by slow-changing chromatin states and by interactions with other transcription factors, which affect their occupancy patterns of potential sites across the genome. These mechanisms lead to emergent discontinuities in function even for transcription factors with minimally changing expression. This is well revealed by diverse lineages of blood cells developing throughout life from hematopoietic stem cells, which use overlapping combinations of transcription factors to drive strongly divergent gene regulation programs. Here, using development of T lymphocytes from hematopoietic multipotent progenitor cells as a focus, recent evidence is reviewed on how binding specificity and dynamics, transcription factor cooperativity, and chromatin state changes impact the effective regulatory functions of key transcription factors including PU.1, Runx1, Notch-RBPJ, and Bcl11b.

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Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2021 Biophysical Society. This is an open access article under the CC BY-NC-ND license ( Received 21 February 2021, Accepted 2 April 2021, Available online 8 April 2021. The author thanks Barbara Wold, Constanze Bonifer, the late Eric H. Davidson, and past and current members of my group for illuminating, critical discussions on this subject. Work on transcription factor functional genomics in the author’s lab has been supported by USPHS grants RC2CA148278, R01AI083514, R01AI095943, R01AI135200, R01HD076915, and R01HL119102. Past support from the A. B. Ruddock Professorship is also gratefully acknowledged. E.V.R. is a member of the Scientific Advisory Board for Century Therapeutics and has served as consultant or advisor to A2 Biotherapeutics and Kite Pharma. Author contributions: E.V.R. wrote the article and made the figures.
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Albert Billings Ruddock ProfessorshipUNSPECIFIED
Issue or Number:19
Record Number:CaltechAUTHORS:20210408-133238795
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Official Citation:Ellen V. Rothenberg, Logic and lineage impacts on functional transcription factor deployment for T-cell fate commitment, Biophysical Journal, Volume 120, Issue 19, 2021, Pages 4162-4181, ISSN 0006-3495,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108664
Deposited By: Tony Diaz
Deposited On:08 Apr 2021 22:25
Last Modified:07 Oct 2021 22:36

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