GSE169401
Genome-wide maps of chromatin state in E12.5 forebrain tissues
The histone methyltransferase complex PRC2 is a crucial chromatin modifier and controls key steps in developmental transitions and cell fate choices. Mutations in PRC2 core subunits are found in Weaver syndrome with craniofacial defects, intellectual disabilities, and often macrocephaly, but its pathogenicity and molecular mechanism are unknown. Here, we examined the role of PRC2/Eed in neural stem/progenitor cells (NSPCs) during cortical neurogenesis We found that Eed is highly expressed in embryonic cerebral cortex and specific deletion of Eed in forebrain reduced the number of upper layer neurons but not deeper layer neurons and ultimately contributed to abnormal cortical development. In addition, our results revealed that PRC2/Eed regulated Hedgehog signaling pathway through activation of Gli3 not dependent on H3K27me3 but H3K27ac. What?s more, Increased Gli3 in NSPCs could reduce Gli1 expression and contribute to the defects of cortical neurogenesis caused by Eed deletion. Finally, Hedgehog signaling activation with small molecule SAG or genetic inactivation of Ptch1 could partially rescue the cortical neurogenesis defects in vivo after Eed depletion. In general, we identified a novel PRC2/Eed-Gli3-Gli1 regulatory axis that is critical for normal cortical neurogenesis. Our findings define a critical function for PRC2/Eed in cortical development and shed light on the genetic basis of intellectual disabilities of neural developmental disorders caused by PRC2/Eed mutation. Overall design: We report the combined application of X-ChIP and CUT&Tag sequencing technology for high-throughput profiling of transcription factor and histone modifications in mammalian cells. By obtaining enough bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of E12.5 wild type and EedcKO forebrains. We find that Eed, histone 3 lysine 27 trimethylation, histone 3 lysine 27 acetylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. These data help us better understand the intrinsic regulatory mechanism of Eed in neurodevelopment. Examination of 2 different groups in E12.5 forbrain tissues..