SETDB1 Orchestrates Metabolic Reprogramming to Regulate Cell State Maintenance and Cell Fate Differentiation

In this study, we explored the function of histone methyltransferase SETDB1 in the development of the mouse dentate gyrus (DG). We discovered that a critical role of Setdb1 in steering the early development path of DG NSCs towards adult neural stem cells and astrocytes destinies. In an effort to delineate the exact molecular mechanisms of aberrant postnatal NSCs and astrocytes caused by Setdb1-deleted NSCs, we utilized a suite of techniques including RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) and Setdb1-Flag Cleavage Under Targets and Tagmentation (CUT&Tag) in both wild-type (WT) and Setdb1-deficient DG samples. Combination of transcriptome and epigenome analysis indicate that COX6B2 as a key target of SETDB1 for regulating maintenance of early postnatal NSCs and differentiation of astrocytes. Taken together, our results highlight the importance of transcriptomic and chromatin landscapes for metabolic reprogramming and identify a exquisite mechanism underlyling the cell state maintenance and cell fate differentiation. Overall design: For all experiments, cells isolated from wild type and Setdb1 cKO mice were collected from mouse dentate gyrus (DG). Single cell sequencing library were prepared using 10x Genomics Chromium Single Cell 3`v3 assays. For bulk RNA-seq, dentate gyri were isolated from P7 mouse brains. Total RNA was extracted using Trizol reagent and applied for RNA sequencing. Setdb1-Flag Cleavage Under Targets and Tagmentation (CUT&Tag) in both wild-type (WT) and Setdb1-deficient DG samples. Assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) in both wild-type (WT) and Setdb1-deficient DG samples.