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Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation
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...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378783/ https://www.ncbi.nlm.nih.gov/pubmed/35983064 http://dx.doi.org/10.3389/fimmu.2022.956156 |
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author | Anderson, Michele K. |
author_facet | Anderson, Michele K. |
author_sort | Anderson, Michele K. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9378783 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93787832022-08-17 Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation Anderson, Michele K. Front Immunol Immunology 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. Frontiers Media S.A. 2022-08-02 /pmc/articles/PMC9378783/ /pubmed/35983064 http://dx.doi.org/10.3389/fimmu.2022.956156 Text en Copyright © 2022 Anderson https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Anderson, Michele K. Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation |
title | Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation |
title_full | Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation |
title_fullStr | Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation |
title_full_unstemmed | Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation |
title_short | Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation |
title_sort | shifting gears: id3 enables recruitment of e proteins to new targets during t cell development and differentiation |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378783/ https://www.ncbi.nlm.nih.gov/pubmed/35983064 http://dx.doi.org/10.3389/fimmu.2022.956156 |
work_keys_str_mv | AT andersonmichelek shiftinggearsid3enablesrecruitmentofeproteinstonewtargetsduringtcelldevelopmentanddifferentiation |