Project description:The lymphoid branch of the immune defense is composed of innate and adaptive immune cells. Using multiple genetic strategies we demonstrate that in the thymus E2A and HEB act in synergy to establish T cell identity and to suppress the aberrant development of innate lymphoid cells that include ILC2 and LTi-like cells. We found that E2A and HEB induce T cell fate by activating the expression of an ensemble of genes encoding for proteins associated with Notch- and pre-TCR signaling and to promote TCRβ antigen receptor assembly. We show that E2A and HEB act in early T progenitors (ETPs) to establish and maintain a T-lineage specific enhancer repertoire, including regulatory elements associated with the Notch1/3 and Rag1/2 gene loci. Based on these and previous observations we propose that the E-Id protein axis specifies innate versus adaptive lymphoid cell fate.
Project description:The lymphoid branch of the immune defense is composed of innate and adaptive immune cells. Using multiple genetic strategies we demonstrate that in the thymus E2A and HEB act in synergy to establish T cell identity and to suppress the aberrant development of innate lymphoid cells that include ILC2 and LTi-like cells. We found that E2A and HEB induce T cell fate by activating the expression of an ensemble of genes encoding for proteins associated with Notch- and pre-TCR signaling and to promote TCRβ antigen receptor assembly. We show that E2A and HEB act in early T progenitors (ETPs) to establish and maintain a T-lineage specific enhancer repertoire, including regulatory elements associated with the Notch1/3 and Rag1/2 gene loci. Based on these and previous observations we propose that the E-Id protein axis specifies innate versus adaptive lymphoid cell fate.
Project description:Background: E2A, encoded by the TCF3 gene locus, belongs to the E protein transcription factor family, which also includes HEB (TCF12) and E2-2 (TCF4), has been suggested to play an important role in leukemogenesis. However, far less is known about the function of E2A in cell-fate regulation of hESCs. Therefore, further understanding of E2A in self-renewal and differentiation of embryonic stem cells may be influenced. Methods: The mRNA profiles of wildtype and E2A knockout embryonic stem cells were generated by RNA-seq technique, in triplicate for each group, using IIIumina Hiseq 2500. Results: A comprehensive human transcriptome map of wild type and E2A knockout embryonic stem cells was provided. Function enrichment, network characteristics and disease association of the differentially expressed genes were analyzed. Conclusion: The dataset could serve as a baseline resource for investigating the potential effects and mechanism of E2A in embryonic stem cells.
Project description:The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the proto-oncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells following restoration of E2A expression, we identify a number of E2A-regulated genes that interfere with oncogenic signaling pathways including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity.
Project description:Nodal signaling, mediated through SMAD transcription factors, is necessary for pluripotency maintenance and endoderm commitment. We have identified a new motif, termed SMAD Complex Associated (SCA) that is bound by SMAD2/3/4 and FOXH1 in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that two bHLH proteins - HEB and E2A - bind the SCA motif at regions overlapping SMAD2/3 and FOXH1. Further, we show that HEB and E2A associate with SMAD2/3 and FOXH1, suggesting they form a complex at critical target regions. This association is biologically important, as E2A is critical for mesendoderm specification, gastrulation, and Nodal signal transduction in Xenopus tropicalis embryos. Taken together, E2A is a novel Nodal signaling cofactor that associates with SMAD2/3 and FOXH1 and is necessary for mesendoderm differentiation.
Project description:The E2A transcription factors promote the development of thymus-seeding cells but it remains unknown whether these proteins play a role in T lymphocyte lineage specification or commitment. By examining E2A-dependent genes in developing T cells, we will address whether these proteins are involved in these processes. DN2 cells from WT and E2A-deficient murine fetal thymi were FACS sorted. Subsequently RNA was extracted, labelled and hybridized to Affymetrix microarrays. The goal of this study is to investigate E2A-dependent genes in developing T cells