Developmental Activation of the TCR {alpha} Enhancer Requires Functional Collaboration among Proteins Bound Inside and Outside the Core Enhancer

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Developmental Activation of the TCR ${alpha}$ Enhancer Requires Functional Collaboration among Proteins Bound Inside and Outside the Core Enhancer¹

Nadège Balmelle²^,3^,, Noelia Zamarreño²^,*, Michael S. Krangel and Cristina Hernández-Munain⁴^,*^,

^* Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain; Basel Institute for Immunology, Basel, Switzerland; and Department of Immunology, Duke University Medical Center, Durham, NC 27710

The TCR ${delta}$ enhancer (E ${delta}$ ) and TCR ${alpha}$ enhancer (E ${alpha}$ ) play critical rolesin the temporal and lineage-specific control of V(D)J recombinationand transcription at the TCR ${alpha}$ ${delta}$ locus, working as a developmentalswitch controlling a transition from TCR ${delta}$ to TCR ${alpha}$ activity duringthymocyte development. Previous experiments using a transgenicreporter substrate revealed that substitution of the 116-bpminimal E ${alpha}$ , denoted T ${alpha}$ 1-T ${alpha}$ 2, for the entire 1.4-kb E ${alpha}$ led to a prematureactivation of V(D)J recombination. This suggested that bindingsites outside of T ${alpha}$ 1-T ${alpha}$ 2 are critical for the strict developmentalregulation of TCR ${alpha}$ rearrangement. We have further analyzed E ${alpha}$ to better understand the mechanisms responsible for appropriatedevelopmental regulation in vivo. We found that a 275-bp E ${alpha}$ fragment,denoted T ${alpha}$ 1-T ${alpha}$ 4, contains all binding sites required for properdevelopmental regulation in vivo. This suggests that developmentallyappropriate enhancer activation results from a functional interactionbetween factors bound to T ${alpha}$ 1-T ${alpha}$ 2 and T ${alpha}$ 3-T ${alpha}$ 4. In support of this,EMSAs reveal the formation of a large enhanceosome complex thatreflects the cooperative assembly of proteins bound to bothT ${alpha}$ 1-T ${alpha}$ 2 and T ${alpha}$ 3-T ${alpha}$ 4. Our data suggest that enhanceosome assemblyis critical for developmentally appropriate activation of E ${alpha}$ in vivo, and that transcription factors, Sp1 and pCREB, mayplay unique roles in this process.

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Developmental Activation of the TCR Enhancer Requires Functional Collaboration among Proteins Bound Inside and Outside the Core Enhancer1

Developmental Activation of the TCR ${alpha}$ Enhancer Requires Functional Collaboration among Proteins Bound Inside and Outside the Core Enhancer¹