Comparison of the PU.1 transcriptional regulome and interactome in human and mouse inflammatory dendritic cells

Abstract

Dendritic cells (DCs) are key immune modulators and are able to mount immune responses or tolerance. DC differentiation and activation imply a plethora of molecular and cellular responses, including transcriptional changes. PU.1 is a highly expressed transcription factor in DCs and coordinates relevant aspects of DC biology. Due to their role as immune regulators, DCs pose as a promising immunotherapy tool. However, some of their functional features, such as survival, activation, or migration, are compromised due to the limitations to simulate in vitro the physiologic DC differentiation process. A better knowledge of transcriptional programs would allow the identification of potential targets for manipulation with the aim of obtaining “qualified” DCs for immunotherapy purposes. Most of the current knowledge regarding DC biology derives from studies using mouse models, which not always find a parallel in human. In the present study, we dissect the PU.1 transcriptional regulome and interactome in mouse and human DCs, in the steady state or LPS activated. The PU.1 transcriptional regulome was identified by performing PU.1 chromatin immunoprecipitation followed by high‐throughput sequencing and pairing these data with RNAsequencing data. The PU.1 interactome was identified by performing PU.1 immunoprecipitation followed by mass spectrometry analysis. Our results portray PU.1 as a pivotal factor that plays an important role in the regulation of genes required for proper DC activation and function, and assures the repression of nonlineage genes. The interspecies differences between human and mouse DCs are surprisingly substantial, highlighting the need to study the biology of human DCs.

Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas

“…6 A). As expected, and previously observed by other groups 29 , 30 , there was a small but consistent enrichment of PU.1 on the promoters of both B7-2 isoforms in the DMSO-treated cells as compared to IgG controls. This enrichment of PU.1 in the control samples supports a role of PU.1 in basal transcription (Fig.…”

“…All the EBV-infected lines showed at least a twofold increase in MIP-1∝/β and/or IP-10 while the KSHV-infected line BCBL-1 and PBMC’s showed no increase in either cytokine (Supplemental file 4 C,D). While there is evidence that MIP-1∝ activates phosphatidylinositol 3-kinase (PI3K) 28 – 30 , and this pathway has been implicated in activating PU.1 which is a known to bind and activate the B7-2 promoter, we did not observe an increase in B7-2 or ICAM-1 upon the addition of recombinant MIP-1∝ (Supplemental file 5 ). As discussed more later, the upregulation of MIP-1∝/β and IP-10 may contribute to tumor responsiveness through additional mechanisms.…”

“…It is known that treating certain cells with Pom induces cereblon-dependent degradation of Ikaros, which is a repressor of the PI3K pathway 31 . Also, the PI3K/AKT pathway has been shown to be involved in activating PU.1, an E26 transformation-specific transcription factor (ETS) 32 that directly binds to the B7-2 promoter and can upregulate its mRNA expression in murine and human dendritic cells 29 , 30 . Pom has also been shown to upregulate PU.1 in myeloma cells 33 .…”

Patterns of Immune Infiltration and the Key Immune-Related Genes in Acute Type A Aortic Dissection in Bioinformatics Analyses

“… 36 As key immune modulators, DCs can mount immune tolerance or responses. 37 The normal intima is thought to be populated by vascular DCs that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. 38 TLR7 stimulation is associated with the expansion of B-cell and Treg response, which may have systemic and local effects on lesions to prevent arterial lipid accumulation and inflammation.…”

NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells

“…SPI1 represents a master TF regulating myeloid development [ 48 ]. Moreover, SPI1 plays a central role in DC differentiation, performing gene regulation and protein interactions [ 22 , 49 ]. SPIB is a main factor for the development of pDCs [ 50 ].…”