The Fanconi anemia (FA) DNA damage response (DDR) pathway regulate important cellular processes such as DNA replication, cell cycle control and DNA damage repair. Here we show that FANCD2, a key member of the FA DDR pathway, interacts with several important components of the germ-cell-specific Prmt5/piRNA pathways that orchestrate the repression of transposable elements (TEs). By using the Pou5f1-eGFP reporter mice, which marks pure populations of primordial germ cells (PGCs), we demonstrate that FA deficiency results in de-repression of TEs, depletion of PGCs, and defective spermatogenesis and oogenesis. Fancd2–KO PGCs exhibited excessive DNA damage and exacerbated apoptosis. Mechanistically, we observed a significant reduction of PRMT5-catalyzed H2A/H4R3me2s marks on the LINE1 TEs in E10.5 PGCs of Fancd2-KO; Pou5f1-eGFP and Fanca-KO;Pou5f1-eGFP embryos. Furthermore, we utilized the Fancd2-KI model to show that Fancd2 and Prmt5 co-occupied the promoter of LINE1 in WT PGCs, and that this co-occupancy was lost in FA-deficient (Fanca-KO) PGCs. These results suggest that the FA pathway takes part in TE repression in early PGCs, likely through a mechanism involving Fancd2-facilitated, Prmt5-catalyzed repressive H2A/H4R3me2s marks on TEs.

Increased flux of glucose through glycolysis is a hallmark of inflammatory macrophages and is essential for optimal effector functions. Solute carrier (SLC) 37A2 is an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter that is highly expressed in macrophages and neutrophils. We demonstrate that SLC37A2 plays a pivotal role in murine macrophage inflammatory activation and cellular metabolic rewiring. Toll-like receptor (TLR) 4 stimulation by lipopolysaccharide (LPS) rapidly increases macrophage SLC37A2 protein expression. SLC37A2 deletion reprograms macrophages to a hyper-glycolytic process and accelerates LPS-induced inflammatory cytokine production, which partially depends on nicotinamide adenine dinucleotide (NAD⁺) biosynthesis. Blockade of glycolysis normalizes the differential expression of pro-inflammatory cytokines between control and SLC37A2 deficient macrophages. Conversely, overexpression of SLC37A2 lowers macrophage glycolysis and significantly reduces LPS-induced pro-inflammatory cytokine expression. In conclusion, our study suggests that SLC37A2 dampens murine macrophage inflammation by down-regulating glycolytic reprogramming as a part of macrophage negative feedback system to curtail acute innate activation.