Abstract
Chromatin architecture proteins HMGNs (High Mobility Group Nucleosome-binding) affect local and global chromatin structure and colocalize with cell-specific regulatory sites and regulate cell identity. The role of HMGN proteins in adipocyte function and energy metabolism is yet to be investigated. Here we report that HMGN1 and HMGN2 double knock-out (DKO) mice on chow diet exhibited decreased weight gain (10%) and total activity with increased food intake and energy expenditure compared to control mice. DKO mice on a high-fat diet also displayed increased food intake and decreased weight gain. We have observed that DKO mice possess less fat mass, which is correlated with decreased WAT size, but not BAT. Histological analysis of WAT from mice revealed smaller adipocytes and increased numbers of cells in DKO, while immunofluorescence analysis indicated more UCP1 in DKO, suggestive of increased WAT browning in DKO mice. Investigations on white preadipocytes or MEF cells differentiation by adipogenic cocktail revealed faster differentiation and elevated UCP1 in DKO cells. Time course RNA seq analysis on in-vitro differentiated adipocytes also confirmed enhanced browning in DKO cells. We further investigated the distribution of active histone marks such as H3K9 acetylation and H3K27 acetylation in adipocytes differentiated from preadipocytes. Our time-course ChIP seq analyses indicated that HMGN’s absence altered both H3K9 and H3K27 acetylation patterns in DKO cells compared to WT. Interestingly, correlation analysis of ChIP seq and RNA seq suggests that DKO preadipocytes and adipocytes lost active chromatin marks at certain white adipocyte-specific enhancers. In summary, loss of HMGN attributes thermogenic character to WAT in DKO mice, thereby contributing to increased energy expenditure, which might protect mice from metabolic disorders—increased white adipocyte browning in DKO is partly by reducing the active histone marks at white specific enhancers, thereby altering white adipocyte identity. Disclosure R. Nanduri: None. T. Furusawa: None. A. Lobanov: None. O. Gavrilova: None. M. Bustin: None. Funding National Cancer Institute
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