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Science. 2019 Jan 3. pii: eaau0583. doi: 10.1126/science.aau0583. [Epub ahead of print]

H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification.

Nicetto D1,2,3, Donahue G1,2,3, Jain T1,2,3, Peng T4,5, Sidoli S2,6, Sheng L2,3, Montavon T7, Becker JS1,2,3, Grindheim JM1,2,3, Blahnik K1,2,3, Garcia BA2,6, Tan K3,4,5,8, Bonasio R2,3, Jenuwein T7, Zaret KS9,2,3.

Author information

1
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
5
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
6
Department of Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
7
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
8
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
9
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. zaret@upenn.edu.

Abstract

Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. H3K9me3-marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein coding genes, in embryologic development, remain elusive. We developed an antibody-independent method to isolate and map compacted heterochromatin from low cell number samples. We discovered high levels of compacted heterochromatin, H3K9me3-decorated, at protein coding genes in early, uncommitted cells at the germ layer stage, undergoing profound rearrangements and reduction upon differentiation, concomitant with cell type-specific gene expression. Perturbation of the three H3K9me3-related methyltransferases revealed a pivotal role for H3K9me3 heterochromatin during lineage commitment at the onset of organogenesis and for lineage fidelity maintenance.

PMID:
30606806
DOI:
10.1126/science.aau0583

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