Pathological LSD1 mutations repress enhancer-mediated gene regulatory networks in early differentiation

LSD1 mutations in patient-derived fibroblasts and reprogrammed pluripotent stem cells shift enhancer-linked transcriptional programs, altering motif accessibilities for 68 transcription factors and dysregulating over 4000 genes.

• Why it matters: The molecular basis of a rare developmental disorder caused by de novo LSD1 mutations is unclear, despite LSD1’s roles in chromatin repression and cancer relevance.
• What they did: Using patient-derived fibroblasts, reprogrammed pluripotent stem cells, and differentiated cells, the study mapped differential expression (over 4000 genes) and motif accessibility changes for 68 TFs, then applied an enhancer-mediated gene regulatory network analysis.
• The result: Transcriptional repressors showed impaired activity, causing erroneous activation of target genes and overall decreases in TF target expression during early differentiation; HDACs inhibition restored gene-expression changes, including the downregulation phenotype.

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