Article ; Online: Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation.
2022 Volume 13, Page(s) 956156
Abstract: Shifting levels of E proteins and Id factors are pivotal in T cell commitment and differentiation, both in the thymus and in the periphery. Id2 and Id3 are two different factors that prevent E proteins from binding to their target gene cis-regulatory ... ...
| Abstract | Shifting levels of E proteins and Id factors are pivotal in T cell commitment and differentiation, both in the thymus and in the periphery. Id2 and Id3 are two different factors that prevent E proteins from binding to their target gene cis-regulatory sequences and inducing gene expression. Although they use the same mechanism to suppress E protein activity, Id2 and Id3 play very different roles in T cell development and CD4 T cell differentiation. Id2 imposes an irreversible choice in early T cell precursors between innate and adaptive lineages, which can be thought of as a railway switch that directs T cells down one path or another. By contrast, Id3 acts in a transient fashion downstream of extracellular signals such as T cell receptor (TCR) signaling. TCR-dependent Id3 upregulation results in the dislodging of E proteins from their target sites while chromatin remodeling occurs. After the cessation of Id3 expression, E proteins can reassemble in the context of a new genomic landscape and molecular context that allows induction of different E protein target genes. To describe this mode of action, we have developed the "Clutch" model of differentiation. In this model, Id3 upregulation in response to TCR signaling acts as a clutch that stops E protein activity ("clutch in") long enough to allow shifting of the genomic landscape into a different "gear", resulting in accessibility to different E protein target genes once Id3 decreases ("clutch out") and E proteins can form new complexes on the DNA. While TCR signal strength and cytokine signaling play a role in both peripheral and thymic lineage decisions, the remodeling of chromatin and E protein target genes appears to be more heavily influenced by the cytokine milieu in the periphery, whereas the outcome of Id3 activity during T cell development in the thymus appears to depend more on the TCR signal strength. Thus, while the Clutch model applies to both CD4 T cell differentiation and T cell developmental transitions within the thymus, changes in chromatin accessibility are modulated by biased inputs in these different environments. New emerging technologies should enable a better understanding of the molecular events that happen during these transitions, and how they fit into the gene regulatory networks that drive T cell development and differentiation. |
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| MeSH term(s) | Cell Differentiation/genetics ; Chromatin ; Cytokines/genetics ; Inhibitor of Differentiation Protein 2/genetics ; Inhibitor of Differentiation Protein 2/metabolism ; Inhibitor of Differentiation Proteins/genetics ; Inhibitor of Differentiation Proteins/metabolism ; Receptors, Antigen, T-Cell/genetics ; Signal Transduction ; T-Lymphocytes/metabolism |
| Chemical Substances | Chromatin ; Cytokines ; Inhibitor of Differentiation Protein 2 ; Inhibitor of Differentiation Proteins ; Receptors, Antigen, T-Cell |
| Language | English |
| Publishing date | 2022-08-02 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2606827-8 |
| ISSN | 1664-3224 ; 1664-3224 |
| ISSN (online) | 1664-3224 |
| ISSN | 1664-3224 |
| DOI | 10.3389/fimmu.2022.956156 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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