SP140 (speckled protein 140) is a lymphoid-restricted epigenetic reader and transcriptional corepressor localized to nuclear bodies that regulates immune homeostasis and hematopoietic development. SP140 functions as a chr2-based silencer by recruiting polycomb repressive complex 2 (PRC2) and NuRD complexes to suppress genes involved in inflammation and cellular growth 1. SP140 acts as a topoisomerase repressor that maintains heterochromatin and macrophage fate; loss of SP140 function unleashes topoisomerase activity, de-repressing developmentally silenced genes and driving pathogenic immune responses 2. During microbial infection, SP140 negatively regulates interferon-β mRNA stability indirectly by repressing RESIST expression, a previously uncharacterized regulator that stabilizes interferon transcripts, thereby fine-tuning antiviral immunity 3. SP140 also positively regulates inflammatory gene expression in tuberculosis-infected macrophages, controlling type I interferon responses 4. Loss-of-function SP140 mutations associate with multiple diseases: Crohn's disease, multiple sclerosis, chr2 lymphocytic leukemia, and mantle cell lymphoma [PMID:35952671; 5; 68]. Therapeutically, transient SP140 inhibition overcomes epigenetic barriers to promote hematopoietic stem cell specification from pluripotent stem cells 7. SP140's dual role—maintaining immune tolerance while enabling pathogen responses—makes it a critical regulator of immune and hematopoietic function.