Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

Grajkowska, Lucja T.; Ceribelli, Michele; Lau, Colleen M.; Warren, Margaret E.; Tiniakou, Ioanna; Higa, Sandra Nakandakari; Bunin, Anna; Haecker, Hans; Mirny, Leonid A.; Staudt, Louis M.; Reizis, Boris

doi:10.1016/j.immuni.2016.11.006

Cited by 90 publications

(75 citation statements)

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“…As the 30 years have gone by, many questions remain: For example, what mechanisms control the ability of HLH proteins to activate lineage-specific gene programs, reprogram differentiated cell types, and faithfully orchestrate antigen receptor assembly. Numerous studies involving all classes of HLH proteins indicate that HLH proteins predominantly bind enhancer elements, recruiting HATs, chromatin remodelers, and coactivators (McMahon et al 1998;Bradney et al 2003;Zhang et al 2004;Forcales et al 2012;Lin et al 2012;Teachenor et al 2012;Bossen et al 2015;Fong et al 2015;Grajkowska et al 2017). Prominent among the factors recruited by HLH proteins is the bromodomain protein BRD4.…”

Section: Resultsmentioning

confidence: 99%

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Helix–loop–helix proteins and the advent of cellular diversity: 30 years of discovery

2019

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Helix-loop-helix (HLH) proteins are dimeric transcription factors that control lineage-and developmental-specific gene programs. Genes encoding for HLH proteins arose in unicellular organisms >600 million years ago and then duplicated and diversified from ancestral genes across the metazoan and plant kingdoms to establish multicellularity. Hundreds of HLH proteins have been identified with diverse functions in a wide variety of cell types. HLH proteins orchestrate lineage specification, commitment, self-renewal, proliferation, differentiation, and homing. HLH proteins also regulate circadian clocks, protect against hypoxic stress, promote antigen receptor locus assembly, and program transdifferentiation. HLH proteins deposit or erase epigenetic marks, activate noncoding transcription, and sequester chromatin remodelers across the chromatin landscape to dictate enhancer-promoter communication and somatic recombination. Here the evolution of HLH genes, the structures of HLH domains, and the elaborate activities of HLH proteins in multicellular life are discussed. Corresponding

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Section: Resultsmentioning

confidence: 99%

“…Id2 expression in pDCs is directly suppressed by the combined activities of E2-2 and MTG16 ( Fig. 5; Grajkowska et al 2017).…”

Section: Hlh Proteins In Hematopoiesismentioning

confidence: 93%

Helix–loop–helix proteins and the advent of cellular diversity: 30 years of discovery

2019

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“…The recent coupling of this long-term hematopoietic progenitor cell line to the CRISPR/Cas9 technology (Hammerschmidt et al, 2018;Roberts et al, 2019) has enabled the creation of new genetically modifiable cell models. During the last few years, expression of Hoxb8 has been used in several studies mainly focused on DC biology (Cabron et al, 2018;Grajkowska et al, 2017;Hammerschmidt et al, 2018;Leithner et al, 2018;Rosas et al, 2011), but only rare studies explored its use to generate surrogate macrophages (Cabron et al, 2018;Roberts et al, 2019;Wang et al, 2006). Only one of these studies directly compared macrophages derived from Hoxb8 progenitors to macrophages derived from bone marrow.…”

Section: Introductionmentioning

confidence: 99%

Genetic engineering of Hoxb8-immortalized hematopoietic progenitors – a potent tool to study macrophage tissue migration

Accarias

Sanchez

Labrousse

et al. 2020

Journal of Cell Science

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Tumor-associated macrophages (TAMs) are detrimental in most cancers. Controlling their recruitment is thus potentially therapeutic. We previously found that TAMs perform protease-dependent mesenchymal migration in cancer, while macrophages perform amoeboid migration in other tissues. Inhibition of mesenchymal migration correlates with decreased TAM infiltration and tumor growth, providing rationale for a new cancer immunotherapy specifically targeting TAM motility. To identify new effectors of mesenchymal migration, we produced ER-Hoxb8-immortalized hematopoietic progenitors (cells with estrogen receptor-regulated Hoxb8 expression), which show unlimited proliferative ability in the presence of estrogen. The functionality of macrophages differentiated from ER-Hoxb8 progenitors was compared to bone marrow-derived macrophages (BMDMs). They polarized into M1-and M2-orientated macrophages, generated reactive oxygen species (ROS), ingested particles, formed podosomes, degraded the extracellular matrix, adopted amoeboid and mesenchymal migration in 3D, and infiltrated tumor explants ex vivo using mesenchymal migration. We also used the CRISPR/Cas9 system to disrupt gene expression of a known effector of mesenchymal migration, WASP (also known as WAS), to provide a proof of concept. We observed impaired podosome formation and mesenchymal migration capacity, thus recapitulating the phenotype of BMDM isolated from Wasp-knockout mice. Thus, we validate the use of ER-Hoxb8-immortalized macrophages as a potent tool to investigate macrophage functionalities.

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“…E2-2 is a basic helix-loop-helix transcription factor that binds the E-box sequence "CANNTG." Binding of E2-2 can either activate or repress target genes [18]. E2-2 is highly expressed in pDCs and at low levels in mDCs and B cells.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

Dewald

Fitzgerald-Bocarsly

2020

Viruses

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Plasmacytoid dendritic cells (pDCs) are innate immune cells and potent producers of interferon alpha (IFNα). Regulation of pDCs is crucial for prevention of aberrant IFN production. Transcription factor E2-2 (TCF4) regulates pDC development and function, but mechanisms of E2-2 control have not been investigated. We used freshly-isolated human peripheral blood mononuclear cells stimulated with toll-like receptor 7, 9, and 4 agonists to determine which factors regulate E2-2. After activation, pDCs decreased E2-2 expression. E2-2 downregulation occurred during the upregulation of costimulatory markers, after maximal IFN production. In congruence with previous reports in mice, we found that primary human pDCs that maintained high E2-2 levels produced more IFN, and had less expression of costimulatory markers. Stimulation of purified pDCs did not lead to E2-2 downregulation; therefore, we investigated if cytokine signaling regulates E2-2 expression. We found that tumor necrosis factor alpha (TNFα) produced by monocytes caused decreased E2-2 expression. All together, we established that primary human pDCs decrease E2-2 in response to TNFα and E2-2 low pDCs produce less IFN but exhibit more costimulatory molecules. Altered expression of E2-2 may represent a mechanism to attenuate IFN production and increase activation of the adaptive immune compartment.

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Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

Cited by 90 publications

References 50 publications

Helix–loop–helix proteins and the advent of cellular diversity: 30 years of discovery

Helix–loop–helix proteins and the advent of cellular diversity: 30 years of discovery

Genetic engineering of Hoxb8-immortalized hematopoietic progenitors – a potent tool to study macrophage tissue migration

Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

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