TY - JOUR
T1 - Activation of mouse Tcrb
T2 - Uncoupling RUNX1 function from its cooperative binding with ETS1
AU - Zhao, Jiang Yang
AU - Osipovich, Oleg
AU - Koues, Olivia I.
AU - Majumder, Kinjal
AU - Oltz, Eugene M.
N1 - Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - T lineage commitment requires the coordination of key transcription factors (TFs) in multipotent progenitors that transition them away from other lineages and cement T cell identity. Two important TFs for the multipotent progenitors to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the TCR β (Tcrβ) locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Eβ, which harbors two RUNX-ETS composite sites. An outstanding issue in understanding T cell gene expression programs is whether RUNX1 and ETS1 have independent functions in enhancer activation that can be dissected from cooperative binding. We now show that RUNX1 is sufficient to activate the endogenous mouse Eβ element and its neighboring 25 kb region by independently tethering this TF without coincidental ETS1 binding. Moreover, RUNX1 is sufficient for long-range promoter-Eβ looping, nucleosome clearance, and robust transcription throughout the Tcrb recombination center, spanning both DβJβ clusters. We also find that a RUNX1 domain, termed the negative regulatory domain for DNA binding, can compensate for the loss of ETS1 binding at adjacent sites. Thus, we have defined independent roles for RUNX1 in the activation of a T cell developmental enhancer, as well as its ability to mediate specific changes in chromatin landscapes that accompany long-range induction of recombination center promoters.
AB - T lineage commitment requires the coordination of key transcription factors (TFs) in multipotent progenitors that transition them away from other lineages and cement T cell identity. Two important TFs for the multipotent progenitors to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the TCR β (Tcrβ) locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Eβ, which harbors two RUNX-ETS composite sites. An outstanding issue in understanding T cell gene expression programs is whether RUNX1 and ETS1 have independent functions in enhancer activation that can be dissected from cooperative binding. We now show that RUNX1 is sufficient to activate the endogenous mouse Eβ element and its neighboring 25 kb region by independently tethering this TF without coincidental ETS1 binding. Moreover, RUNX1 is sufficient for long-range promoter-Eβ looping, nucleosome clearance, and robust transcription throughout the Tcrb recombination center, spanning both DβJβ clusters. We also find that a RUNX1 domain, termed the negative regulatory domain for DNA binding, can compensate for the loss of ETS1 binding at adjacent sites. Thus, we have defined independent roles for RUNX1 in the activation of a T cell developmental enhancer, as well as its ability to mediate specific changes in chromatin landscapes that accompany long-range induction of recombination center promoters.
UR - http://www.scopus.com/inward/record.url?scp=85026196127&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1700146
DO - 10.4049/jimmunol.1700146
M3 - Article
C2 - 28637900
AN - SCOPUS:85026196127
SN - 0022-1767
VL - 199
SP - 1131
EP - 1141
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -