Rapid Fire & Poster Presentation 39th Annual Lorne Genome Conference 2018

Canonical PRC2 function is essential for mammary gland development and affects chromatin compaction in mammary organoids (#205)

Ewa M Michalak 1 2 , Michael J.G Milevskiy 1 , Rachel M Joyce 1 , Johanna F Dekkers 1 , Paul R Jamieson 1 , Bhupinder Pal 1 , Yifang Hu 1 , Stuart H Orkin 3 , Warren S Alexander 1 , Geoffrey J Lindeman 1 , Gordon K Smyth 1 , Jane E Visvader 1
  1. Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
  2. PETER MACCALLUM CANCER CENTRE, Melbourne, VIC, Australia
  3. Dana Farber Cancer Instiute, Boston, USA

Distinct transcriptional states are maintained through organization of chromatin, resulting from the sum of numerous repressive and active histone modifications, into tightly packaged heterochromatin versus more accessible euchromatin. PRC2 is the main mammalian complex responsible for Histone 3 lysine 27 tri-methylation (H3K27me3), and is integral to chromatin organization. Using in vitro and in vivo studies, we show that deletion of Suz12, a core component of all PRC2 complexes, results in loss of H3K27me2/me3, completely blocks normal mammary gland development and profoundly curtails progenitor activity in 3D organoid cultures. Through the application of mammary organoids to bypass the severe phenotype associated with Suz12 loss in vivo, we have explored gene expression and chromatin structure in wildtype and Suz12-deleted basal-derived organoids. Analysis of organoids led to the identification of lineage-specific changes in gene expression and chromatin structure, inferring cell-type specific PRC2-mediated gene silencing of the chromatin state. These data indicate that canonical PRC2 function is essential for development of the mammary gland through the repression of alternate transcription programs and maintenance of chromatin states.