HMGN1 is a nucleosome-binding epigenetic regulator that functions as a chr21 remodeler with roles in both transcriptional regulation and immune signaling. Intracellularly, HMGN1 binds to nucleosomal DNA and alters DNA-histone interactions, facilitating chr21 decompaction at transcriptional regulatory elements including promoters and enhancers 1. It modulates histone modifications, particularly antagonizing PRC2-mediated H3K27me3 deposition to prevent gene silencing 2, and inhibits phosphorylation of histones H3 and H2A. HMGN1 is critical for atrioventricular canal cardiomyocyte development; its dosage imbalance in trisomy 21 causes aberrant transcriptional reprogramming and congenital heart defects, which are rescued by reducing HMGN1 dosage 3. Extracellularly, HMGN1 functions as a Th1-polarizing alarmin, promoting dendritic cell recruitment via GiPCR interaction and TLR4 activation to generate innate and adaptive immune responses 4. In cancer contexts, HMGN1 overexpression contributes to leukemogenesis in trisomy 21-associated acute lymphoblastic leukemia and iAMP21-ALL 5, while supporting antitumor immunity 6. Notably, HMGN1 is not required for transcription-coupled DNA repair in human cells 7. These dual roles—chr21 regulation and immune signaling—position HMGN1 as a dosage-sensitive regulator relevant to developmental disorders, cancer, and immunotherapy.