Astrocyte circadian regulation in neurodegeneration: in vivo BMAL1 occupancy mapping using MACS-Calling Cards

Wild-type-specific BMAL1 binding was enriched near genes involved in circadian regulation and astrocyte differentiation, whereas disease-specific sites lacked coherent functional enrichment. Consistent with these changes, RNA-seq of sorted astrocytes revealed reduced expression of mature astrocyte markers in CLN3Δex7/8 mice. To define the mechanisms underlying BMAL1 retargeting in CLN3Δex7/8 astrocytes, we tested whether changes in chromatin accessibility could explain disease-associated gains and losses of BMAL1 binding.

Although chromatin accessibility was broadly remodeled, differential accessibility did not predict BMAL1 binding gains or losses. Instead, motif analyses supported a model in which loss of normal cooperative transcription factor partnerships contributes to BMAL1 retargeting. Together, these findings demonstrate that MACS-CC enables in vivo TF occupancy mapping in astrocytes and reveals the mechanisms behind early rewiring of circadian regulatory programs within a model of neurodegeneration.