Heroin addiction modulates transcription factor binding in regulatory regions of the human putamen

The ongoing opioid crisis underscores the need to elucidate the neurobiology of addiction for improved treatments. Dynamic transcription factor (TF) binding is a key driver of substance use disorders (SUDs), yet its genome-wide patterns in human brain cell types remain poorly defined. We performed a computational re-analysis of publicly available ATAC-seq data (PRJNA561094) from post-mortem putamen samples of heroin users and matched non-users, where we profiled chromatin accessibility analyzing neuronal and glial cells separately. Genome-wide TF binding sites were identified and quantified, followed by footprinting and differential binding analyses. Co-occurrence analysis was applied to identify TF pairings associated with SUD-related genes. Neurons from heroin users exhibited 38 TFs with altered binding and footprinting, while glia showed 11 differentially bound TFs, primarily from the FOS, JUN, and ZNF families. NRF1 and KLF15 were differentially bound in both cell types. These TFs were linked to SUD-associated genes and activation of neuroinflammatory, neurohormonal, and S100 pathway genes. Co-occurrence analysis identified five TF pairs in user neurons and thirteen in non-user glia interacting with SUD-related genes and driving neuroinflammatory signaling. Overall, our findings reveal distinct alterations in TF binding accessibility and co-occurrence networks in heroin users' neurons and glia, implicating transcriptional dysregulation in addiction-related neuroinflammation and neurohormonal activity.