The MYCL and MXD1 transcription factors regulate the fitness of murine dendritic cells

Abstract

We previously found that MYCL is required by aBatf3-dependent classical dendritic cell subset (cDC1) for optimal CD8 T cell priming, but the underlying mechanism has remained unclear. The MAX-binding proteins encompass a family of transcription factors with overlapping DNA-binding specificities, conferred by a C-terminal basic helix-loop-helix domain, which mediates heterodimerization. Thus, regulation of transcription by these factors is dependent on divergent N-terminal domains. The MYC family, including MYCL, has actions that are reciprocal to the MXD family, which is mediated through the recruitment of higher-order activator and repressor complexes, respectively. As potent proto-oncogenes, models of MYC family function have been largely derived from their activity at supraphysiological levels in tumor cell lines. MYC and MYCN have been studied extensively, but empirical analysis of MYCL function had been limited due to highly restricted, lineage-specific expression in vivo. Here we observed thatMyclis expressed in immature cDC1s but repressed on maturation, concomitant withMxd1induction in mature cDC1s. We hypothesized that MYCL and MXD1 regulate a shared, but reciprocal, transcriptional program during cDC1 maturation. In agreement, immature cDC1s inMycl−/−-deficient mice exhibited reduced expression of genes that regulate core biosynthetic processes. Mature cDC1s fromMxd1−/−mice exhibited impaired ability to inhibit the transcriptional signature otherwise supported by MYCL. The present study reveals LMYC and MXD1 as regulators of a transcriptional program that is modulated during the maturation ofBatf3-dependent cDC1s.

Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

“…Even at the lowest r value (≥0.5), transcription factor genes identified as specific to particular tissue-specific MPS populations made few additional connections, indicating that local adaptation is dependent on highly correlated and regulated expression of a small cohort of transcription factors. Nevertheless, associations that become evident at lower r values may identify combinatorial interactions in particular cell populations: Mycl , associated with DC fitness [ 152 ], was weakly correlated with Irf8 and Zbtb46 ; Cebpb with Nfil3 ; and interferon-related transcription factors ( Batf2 , Irf1/7/9 , Stat1/2 ) were connected at the threshold of 0.5 ( S3 Data ).…”

PP2Cδ Controls the Differentiation and Function of Dendritic Cells Through Regulating the NSD2/mTORC2/ACLY Pathway

“…The results showed that either blocking mitochondrial pyruvate entry or inhibiting catalytic activity of ACLY corrected, though to different extent, the expression of genes characterizing hyperactivated DCs upon PP2Cd deletion (Figure 6L). The results showed that a network of signature genes including the activation and metabolism-related genes (il-6, il-1b, cd80, h2-iab, and ccr7), mitochondrial and glycolytic metabolism-related genes (pgc-1a, hk-2, and pkm2), and DC-specifying transcription factors (irf4, pu.1, c-myc, nr4a1, and nr4a3) (53)(54)(55)were substantially altered upon these treatments. We thus proposed that ACLY-driven metabolic-epigenetic flux, downstream of the PP2Cd/mTORC2 pathway, was critically involved in the gene program for DC identity.…”

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

“…Even at the lowest r value (≥ 0.5), transcription factor genes identified as specific to particular tissue-specific MPS populations made few additional connections, indicating that local adaptation is dependent on highly-correlated and regulated expression of a small cohort of TF. Nevertheless, associations that become evident at lower r value may identify combinatorial interactions in particular cell populations; Mycl, associated with DC fitness ( [135] was weaklycorrelated with Irf8 and Zbtb46; Cebpb with Nfil3 and interferon-related transcription factors (Batf2, Irf1/7/9, Stat1/2) were connected at the threshold of 0.5 ( Table S3).…”