Abstract Several studies have reported that hemoglobin is expressed in neurons in the rodent and human brain, however the function of hemoglobin in these cells hasn't been clearly defined. The long term goal of this research is to better understand why hemoglobin is expressed in cells other than red blood cells. The hemoglobin and subunits (Hba and Hbb) are expressed in neurons in the brain, but only Hbb is localized to the nucleus. In this proposal our objective is to understand why Hbb is expressed in the nucleus and to uncover mechanisms involved in Hbb signaling. We have found that Hbb interacts with chromatin where it inhibits the activity of the KDM5B histone demethylase by sequestering oxygen required for KDM5B activity. Hbb mediated inhibition of KDM5B results in increased levels of H3K4me3, a histone mark that activates transcription. The aims of this proposal will test the hypothesis: that Hbb regulates chromatin and transcription in the brain to adapt to metabolic demands. In aim 1: ChIP- seq will be employed to find out where Hbb is bound to chromatin and which genes are regulated by Hbb signaling in primary neuronal cultures. In aim 2: Effects of Hbb on bioenergetics will be assessed with Seahorse respirometry. Aim 3: will test the role of exercise on regulation of Hbb signaling pathways and energy metabolism in the brain. The proposed study will increase the understanding of mechanisms involved in regulating the chromatin landscape and gene expression related to balancing energy metabolism needs.