Biomedical subjects

Isaac Engel

Publications and source records attributed to Isaac Engel.

5 recordsLinked to original sources

PubMed2014

Jarid2 is induced by TCR signalling and controls iNKT cell maturation.

Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.

Animals↗

PubMed2006

Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development.

In maturing T lineage cells, the helix-loop-helix protein E47 has been shown to enforce a critical proliferation and developmental checkpoint commonly referred to as beta selection. To examine how E47 regulates cellular expansion and developmental progression, we have used an E2A-deficient lymphoma cell line and DNA microarray analysis to identify immediate E47 target genes. Hierarchical cluster analysis of gene expression patterns revealed that E47 coordinately regulates the expression of genes involved in cell survival, cell cycle progression, lipid metabolism, stress response, and lymphoid maturation. These include Plcgamma2, Cdk6, CD25, Tox, Gadd45a, Gadd45b, Gfi1, Gfi1b, Socs1, Socs3, Id2, Eto2, and Xbp1. We propose a regulatory network linking Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-mediated signaling, E47, and suppressor of cytokine signaling (SOCS) proteins in a common pathway. Finally, we suggest that the aberrant activation of Cdk6 in E47-deficient T lineage cells contributes to the development of lymphoid malignancy.

Cell Cycle↗

PubMed2006

Interplay between RORgammat, Egr3, and E proteins controls proliferation in response to pre-TCR signals.

The response of thymocytes to pre-T cell receptor (pre-TCR) signaling includes proliferation and gene rearrangement, two cellular processes that are incompatible. The control of proliferation by pre-TCR signals depends on the activities of the transcription factors RORgammat, Egr3, E12, and E47. Here, we describe a regulatory network in which interplay between these factors ensures transient proliferation that is temporally distinct from gene rearrangement. RORgammat expression was elevated after pre-TCR signaling, and RORgammat promoted gene rearrangement in CD4+, CD8+ cells by inhibiting cell division, promoting survival via Bcl-X(L), and inducing Rag2. Egr3 was transiently induced by pre-TCR signals and promoted a distinct proliferative phase by reducing E protein-dependent RORgammat expression and interacting with RORgammat to prevent induction of target genes. After Egr3 subsided, the expression and function of RORgammat increased. Thus, transient induction of Egr3 delays the effects of RORgammat and enables pre-TCR signaling to induce both proliferation and gene rearrangement.

Animals↗

PubMed2003

E2A proteins enforce a proliferation checkpoint in developing thymocytes.

E2A proteins regulate multiple stages of thymocyte development and suppress T-cell lymphoma. The activity of E2A proteins throughout thymocyte development is modulated by signals emanating from the pre-TCR and TCR. Here we demonstrate that E2A is required for the complete arrest in both differentiation and proliferation observed in thymocytes with defects in proteins that mediate pre-TCR signaling, including LAT, Lck and Fyn. We show that E2A proteins are required to prevent the accumulation of TCRbeta negative cells beyond the pre-TCR checkpoint. E2A-deficient thymocytes also exhibit abnormal cell-cycle progression prior to pre-TCR expression. Furthermore, we demonstrate that E47 can act in concert with Bcl-2 to induce cell-cycle arrest in vitro. These observations indicate that E2A proteins function during early thymocyte development to block cell-cycle progression prior to the expression of TCRbeta. In addition, these data provide further insight into how deficiencies in E2A lead to T lymphoma.

Animals↗

PubMed2002

Disruption of pre-TCR expression accelerates lymphomagenesis in E2A-deficient mice.

The helix-loop-helix proteins E47 and E12, which are encoded by the E2A gene, regulate several stages of T cell development. In addition, mice deficient for E2A are highly susceptible to thymic lymphoma. Here we report that the development of lymphoma in E2A-deficient mice did not require pre- and recombinase-activating gene expression. Rather, we found that, whereas illegitimate DNA rearrangement did not play a major role in the development of these lymphomas, defects that prevented pre-T cell antigen receptor expression tended to accelerate lymphomagenesis in E2A-deficient mice. These data and previous observations also provide insight into the role of Notch in lymphoma development. Specifically, we propose that Notch activation indirectly modulates E2A activity through induction of pre-Talpha expression, ultimately leading to the development of lymphoma.

Animals↗